Patent application title: NEUREGULIN ISOFORMS, NEUREGULIN POLYPEPTIDES AND USES THEREOF
Inventors:
Thierry Baussant (Bellearde Sur Valserine, FR)
Daniel Bach (Geneve, CH)
André Schrattenholz (Mainz, DE)
IPC8 Class: AC07K14475FI
USPC Class:
514 83
Class name: Peptide (e.g., protein, etc.) containing doai growth factor or derivative affecting or utilizing nerve tissue or nerve cell growth affecting
Publication date: 2015-03-19
Patent application number: 20150080302
Abstract:
The present invention relates to new therapeutic and diagnostic uses of
soluable neuregulin-1 isoforms and polypeptides, particularly
neurological disorders.Claims:
1. A polypeptide, wherein the polypeptide comprises or consists of an
EGF-like domain (EGFLD1) selected from the group consisting of SEQ ID NO:
140-146, wherein said EGF-like domain may comprise up to five single
amino acid deletions, insertions and/or mutations and wherein said
EGF-like domain optionally comprises up to 30 additional amino acids at
its C- and/or N-terminus.
2. The polypeptide according to claim 1, wherein the EGF-like domain (EGFLD1) is selected from the group consisting of SEQ ID NO: 147-153 and wherein said EGF-like domain may comprise up to 13 single amino acid deletions, insertions and/or mutations.
3. The polypeptide according to claim 1, wherein the polypeptide further comprises at least one additional EGF-like domain, each independently selected from the group consisting of SEQ SD NO: 140-153, wherein each additional EGF-like domain may comprise up to 13 single amino acid deletions, insertions and/or mutations.
4. The polypeptide according to claim 1, wherein the polypeptide comprises at least a second EGF-like domain (EGFLD2) selected from the group consisting of SEQ ID NO: 140-153, wherein the second EGF-like domain may comprise up to 13 single amino acid deletions, insertions and/or mutations.
5. The polypeptide according to claim 1, wherein the polypeptide further comprises a heparin binding domain (HBD).
6. The polypeptide according to claim 5, wherein the heparin binding domain has an amino acid sequence according to any of SEQ ID NO: 154-157 and wherein the heparin binding domain may comprise up to 12 single amino acid deletions, insertions and/or mutations.
7. The polypeptide according to claim 5, wherein said heparin binding domain is at the N-terminus or the C-terminus of the EGF-like domain.
8. The polypeptide according to claim 4, wherein the polypeptide further comprises a linker between the EGF-like domain EGFLD 1 and the second EGF-like domain EGFLD2, between any two or more neighbouring EGF-like domains, between said heparin binding domain and said EGF-like domain EGFLD 1 and/or between said heparin binding domain and said second EGF-like domain EGFLD2.
9. The polypeptide according to claim 8, wherein the polypeptide has the structure: EGFLD 1-linker-EGFLD2, HBD-linker-EGFLD 1-linker-EGFLD2, EGFLD 1-linker-HBD-linker-EGFLD2, or EGFLD 1-linker-EGFLD2-linker-HBD,
10. The polypeptide according to claim 8, wherein each linker is individually selected from a covalent bond, a chemical linker and a polypeptide preferably having a length of up to 45 amino acids.
11. The polypeptide according to claim 10, wherein the linker has an amino acid sequence according to SEQ ID NO: 158, wherein the linker may comprise up to fifteen single amino acid deletions, insertions and/or mutations.
12. The polypeptide according to claim 1, wherein the polypeptide specifically binds to the erbB3 receptor (SEQ ID NO: 159) and/or erbB4 receptor (SEQ ID NO: 160).
13. Pharmaceutical composition comprising a polypeptide of claim 1.
14. The pharmaceutical composition according to claim 13, further comprising a medicament for the treatment of a neurological condition preferably a medicament selected from the group consisting of a compound affecting catecholamine metabolism, an acetylcholine esterase inhibitor, a MAO-B- or COMT-inhibitor, a memantine-type channel blocker, a dopamine or serotonine receptor agonist, a dopamine or serotonine receptor antagonist, a catecholamine or serotonine reuptake inhibitor, an antipsychotic medication, a drug for the treatments of Alzheimer's or Parkinson's disease and a medicament against schizophrenia, bipolar disorder or depression.
15. A polypeptide of claim 1 for use in the prophylaxis or treatment of a neurological condition.
16. The polypeptide of claim 15, wherein the neurological condition is selected from the group of schizophrenia, in particular cognition-related aspects of schizophrenia, bipolar disorder and depression; Parkinson's disease; Alzheimer's disease; epilepsy; MS; ALS; stroke; traumatic brain injury and spinal chord injury.
17. Use of a polypeptide according to claim 1 or a polynucleotide encoding said polypeptide for inducing differentiation of a cell.
18. Antibody capable of specifically binding to a protein selected from the group consisting of 14-3-3-zeta (SEQ ID NOs:58, 133), 14-3-3-epsilon (SEQ ID NOs:59, 134), N-ethylmaleimide sensitive factor (SEQ ID NOs:50, 124), Aldolase A, fructose-bisphosphate (SEQ ID NOs:2, 68): Aldolase C, fructose-bisphosphate (SEQ ID NO:3, 69); Triosephosphate isomerase 1 (SEQ ID NOs:4, 65, 70); similar to Glyceraldehyde-3-phosphate dehydrogenaseisoform 1 (SEQ ID NOs:5, 71, 72); Enolase 1, alpha non-neuron (SEQ ID NOs:6, 73); Enolase 2, gamma neuronal (SEQ ID NOs:7, 74); Lactate dehydrogenase B (SEQ ID NOs:8, 75); Glycerol phosphate dehydrogenase 2, mitochondrial (SEQ ID NOs:9, 76, 77); Glutamate-ammonia ligase (Glutamine synthetase) (SEQ ID NOs: 10, 78, 79); Dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase complex) (SEQ ID NOs: 11, 80, 66); Isocitrate dehydrogenase 3 (NAD+) alpha, isoform CRA_e (SEQ ID NOs: 12, 81); Malate dehydrogenase, cytoplasmic (SEQ ID NOs: 13, 82); NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8 (SEQ ID NOs: 14, 83); NADH dehydrogenase (ubiquinone) Fe-S protein 1 (SEQ ID NOs: 15, 84, 67); NADH dehydrogenase (ubiquinone) Fe-S protein 8 (SEQ ID NOs: 16, 85); Ubiquinol-cytochrome-c reductase complex core protein 1 (SEQ ID NOs: 17, 86); ATP synthase, H+ transporting, mitochondrial F0 complex, subunit d (SEQ ID NOs: 18, 87, 88); Creatine kinase, brain (SEQ ID NOs: 19, 89); Heat shock protein 8 (SEQ ID NOs:20, 90, 91); Heat shock protein 9 (SEQ ID NOs:21, 92); Hsp70 homolog perinuclear form (mortalin mot-2) (SEQ ID NO:22); Protein disulfide isomerase associated 3 (SEQ ID NOs:23, 93); ATPase, H+ transporting, lysosomal VI subunit A (SEQ ID NOs:24, 94); Proteasome 26S subunit, ATPase, 4 (SEQ ID NOs:25, 95, 96); Proteasome subunit alpha type-2 (SEQ ID NOs:26, 97); Ubiquitin carboxy-terminal hydrolase L1, isoform CRA_b (SEQ ID NOs:27, 98); Valosin containing protein, isoform CRA_b (SEQ ID NOs:28, 99); 3-Hydroxyisobutyrate dehydrogenase (SEQ ID NOs:29, 100); Biphenyl hydrolase-like (SEQ ID NOs:30, 101); Haloacid dehalogenase-like hydrolase domain containing 2 (SEQ ID NOs:31, 102); Beta-actin (aa 27-375) (SEQ ID NOs:32, 103); Gamma-actin (SEQ ID NOs:33, 104); Profilin 2, isoform CRA_b (SEQ ID NOs:34, 105, 106); Transgelin 3 (SEQ ID NOs:35, 107); Annexin A6, isoform CRA_b (SEQ ID NOs:36, 108, 109); Internexin neuronal intermediate filament protein, alpha (SEQ ID NOs:37, 110); Neurofilament, light polypeptide (SEQ ID NOs:38, 111); Glial fibrillary acidic protein (SEQ ID NOs:39, 112, 113); Tubulin, alpha IB (SEQ ID NOs:40, 114); Tubulin, beta (SEQ ID NOs:41, 115); Tubulin, beta 3 (SEQ ID NOs:42, 116); Dihydropyrimidinase-like 2 (SEQ ID NOs:43, 117); Dihydropyrimidinase-like 4, isoform CRA_c (SEQ ID NOs:44, 118); Brain abundant, membrane attached signal protein 1 (SEQ ID NOs:45, 119); RAB1B, member RAS oncogene family; isoform CRA_a (SEQ ID NOs:46, 120); RAB3A, member RAS oncogene family (SEQ ID NOs:47, 121); RAB6A, member RAS oncogene family (SEQ ID NOs:48, 122); Guanosine diphosphate dissociation inhibitor 1 (SEQ ID NOs:49, 123); Phospholipase C-alpha (SEQ ID NOs:51, 125); Calcineurin B5 type I (SEQ ID NOs:52, 126, 127); Calbindin-28K (SEQ ID NOs:53, 128); Calretinin (SEQ ID NOs:54, 129); Visinin-like 1 (SEQ ID NOs:55, 130); Chloride intracellular channel 4 (mitochondrial) (SEQ ID NOs:58, 131); mCG7191 (Rat Kinase Inhibitor Protein (RKIP)) (SEQ ID NOs:57, 132); Peroxiredoxin 1 (SEQ ID NOs:60, 135); Peroxiredoxin 3 (SEQ ID NOs:61, 136); Pyridoxal (pyridoxine, vitamin B6) kinase (SEQ ID NOs:62, 137); and Guanine nucleotide binding protein, alpha o isoform B (SEQ ID NOs:63, 138, 139) for use as a diagnostic.
19. Method of diagnosing a disease comprising (i) determining in vitro in an isolated tissue explant or isolated body fluid of a subject the quantity of a protein having at least 90% amino acid sequence identity with a protein selected from the group consisting of 14-3-3-zeta (SEQ ID NOs:58, 133), 14-3-3-epsilon (SEQ ID NOs:59, 134), N-ethylmaleimide sensitive factor (SEQ ID NOs:50, 124), Aldolase A, fructose-bisphosphate (SEQ ID NOs:2, 68); Aldolase C, fructose-bisphosphate (SEQ ID NO:3, 69); Triosephosphate isomerase 1 (SEQ ID NOs:4, 65, 70); similar to Glyceraldehyde-3-phosphate dehydrogenaseisoform 1 (SEQ ID NOs:5, 71, 72); Enolase 1, alpha non-neuron (SEQ ID NOs:6, 73); Enolase 2, gamma neuronal (SEQ ID NOs:7, 74); Lactate dehydrogenase B (SEQ ID NOs:8, 75); Glycerol phosphate dehydrogenase 2, mitochondrial (SEQ ID NOs:9, 76, 77); Glutamate-ammonia ligase (Glutamine synthetase) (SEQ ID NOs: 10, 78, 79); Dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase complex) (SEQ ID NOs: 11, 80, 66); Isocitrate dehydrogenase 3 (NAD+) alpha, isoform CRA_e (SEQ ID NOs: 12, 81); Malate dehydrogenase, cytoplasmic (SEQ ID NOs: 13, 82); NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8 (SEQ ID NOs: 14, 83); NADH dehydrogenase (ubiquinone) Fe-S protein 1 (SEQ ID NOs: 15, 84, 67); NADH dehydrogenase (ubiquinone) Fe-S protein 8 (SEQ ID NOs: 16, 85); Ubiquinol-cytochrome-c reductase complex core protein 1 (SEQ ID NOs: 17, 86); ATP synthase, H+ transporting, mitochondrial F0 complex, subunit d (SEQ ID NOs: 18, 87, 88); Creatine kinase, brain (SEQ ID NOs: 19, 89); Heat shock protein 8 (SEQ ID NOs:20, 90, 91); Heat shock protein 9 (SEQ ID NOs:21, 92); Hsp70 homolog perinuclear form (mortalin mot-2) (SEQ ID NO:22); Protein disulfide isomerase associated 3 (SEQ ID NOs:23, 93); ATPase, H+ transporting, lysosomal VI subunit A (SEQ ID NOs:24, 94); Proteasome 26S subunit, ATPase, 4 (SEQ ID NOs:25, 95, 96); Proteasome subunit alpha type-2 (SEQ ID NOs:26, 97); Ubiquitin carboxy-terminal hydrolase LI, isoform CRA_b (SEQ ID NOs:27, 98); Valosin containing protein, isoform CRA_b (SEQ ID NOs:28, 99); 3-Hydroxyisobutyrate dehydrogenase (SEQ ID NOs:29, 100): Biphenyl hydrolase-like (SEQ ID NOs:30, 101); Haloacid dehalogenase-like hydrolase domain containing 2 (SEQ ID NOs:31, 102); Beta-actin (aa 27-375) (SEQ ID NOs:32, 103); Gamma-actin (SEQ ID NOs:33, 104); Profilin 2, isoform CRA_b (SEQ ID NOs:34, 105, 106); Transgelin 3 (SEQ ID NOs:35, 107); Annexin A6, isoform CRA_b (SEQ ID NOs:38, 108, 109); Internexin neuronal intermediate filament protein, alpha (SEQ ID NOs:37, 110); Neurofilament, light polypeptide (SEQ ID NOs:38, 111); Glial fibrillary acidic protein (SEQ ID NOs:39, 112, 113); Tubulin, alpha IB (SEQ ID NOs:40, 114); Tubulin, beta (SEQ ID NOs:41, 115); Tubulin, beta 3 (SEQ ID NOs:42, 116); Dihydropyrimidinase-like 2 (SEQ ID NOs:43, 117); Dihydropyrimidinase-like 4, isoform CRA_c (SEQ ID NOs:44; 118); Brain abundant, membrane attached signal protein 1 (SEQ ID NOs:45, 119); RAB1B, member RAS oncogene family; isoform CRA_a (SEQ ID NOs:46, 120); RAB3A, member RAS oncogene family (SEQ ID NOs:47, 121); RAB6A, member RAS oncogene family (SEQ ID NOs:48, 122); Guanosine diphosphate dissociation inhibitor 1 (SEQ ID NOs:49, 123); Phospholipase C-alpha (SEQ ID NOs:51, 125); Calcineurin B, type I (SEQ ID NOs:52, 126, 127); Calbindin-28K (SEQ ID NOs:53, 128); Calretinin (SEQ ID NOs:54, 129); Visinin-like 1 (SEQ ID NOs:55, 130); Chloride intracellular channel 4 (mitochondrial) (SEQ ID NOs:56, 131); mCG7191 (Raf Kinase Inhibitor Protein (RKIP)) (SEQ ID NOs:57, 132): Peroxiredoxin 1 (SEQ ID NOs:60, 135); Peroxiredoxin 3 (SEQ ID NOs:61, 136); Pyridoxal (pyridoxine, vitamin B6) kinase (SEQ ID NOs:62, 137); and Guanine nucleotide binding protein, alpha o isoform B (SEQ ID NOs:63, 138, 139) or a polynucleotide encoding said protein; (ii) optionally determining whether the amount of protein differs from the amount of the corresponding protein quantified in a healthy subject; and (iii) optionally correlating a change in expression of said protein when compared with the expression of said protein in a healthy subject with a neurological disease which is preferably selected from the group consisting of Alzheimer's disease, multiple sclerosis or brain damage and Parkinsons' disease.
20. A polynucleotide encoding a polypeptide of claim 1.
Description:
[0001] The present invention relates to new therapeutic and diagnostic
uses of soluble neuregulin-1 isoforms and polypeptides, particularly
neurological disorders.
BACKGROUND OF THE INVENTION
[0002] The neuregulin (Nrg) family of growth and differentiation factors play a crucial role in development and plasticity of the nervous system. Four genes (NRG-1 to NRG-4) are translated to diverse transmembrane and soluble isoforms. NRG-1 encodes 15 known Nrg1 isoforms with distinct time- and tissue-specific expression patterns. The extracellular domain (ECD) of Nrg1 is cleaved by β-amyloid converting enzyme-1 and released into the intercellular space to act as paracrine trophic factor. The ECD contains an epidermal growth factor (EGF)-like motive to activate ErbB3 and ErbB4 receptors by dimerization and tyrosin phosphorylation. ErbB4 is a functional receptor tyrosine kinase, while ErbB3 depends on hetero-dimerization to transduce signals.
[0003] Nrg1 has been genetically linked to schizophrenia, a neurodevelopmental mental disorder with imbalances in dopaminergic neurotransmission. Several lines of evidence suggest that Nrg1 affects dopamine-signaling. In fact, human and rodent midbrain dopaminergic neurons highly express ErbB4 throughout development into adulthood. An N-terminally truncated ECD of human Nrg1β1 (nucleotides 46-634, 25.4 kDa) passes the immature blood-brain barrier (BBB) in neonatal mice, activates midbrain ErbB4 receptors, increases the enzymatic activity of tyrosine hydroxylase (TH, the rate-limiting enzyme of dopamine biosynthesis) and induces a persistent hyper-dopaminergic state; its this work, Nrg1β1-treatment coincided with the postnatal phase of ontogenic cell death and axonal differentiation of the mesencephalic dopaminergic system, suggesting that Nrg1β1 acts as neurotrophic factor during development.
[0004] Also in rodent adults, direct intracerebral infusion of the entire ECD (Ser2-Lys246, 26.9 kDa) of human Nrg1β1 into the hippocampus or of the EGF-like domain only (Thr176-Lys246, 8 kDa) into the striatum transiently increases local dopamine release, indication that some reactivity of the dopaminergic system to Nrg1β1 persists into adulthood.
[0005] Since the adult dopaminergic system is subject to progressive degeneration in various neurological disorders, e.g., Parkinson's disease (PD), leading to a disabling hypokinetic-rigid syndrome15, there is a need in the art to provide new therapeutic strategies promoting neuroprotection and preventing neurodegeneration resulting in a loss of neurons.
SUMMARY OF THE INVENTION
[0006] Based on in vivo, in vitro and in silico data the inventors have found that neuregulin-1 isoforms and neuregulin polypeptides, e.g. of Nrg1β1 as described herein, are (i) capable of providing neuroprotection of, e.g., dopaminergic neurons, (ii) exhibit an improved receptor binding affinity and/or (iii) are capable of inducing cell differentiation of, e.g., erbB4- and/or erbB3-expressing cells that do not express neuromelanin and tyrosine hydroxylase. These cells were shown to transform into e.g. dopaminergic neurons when contacted with a polypeptide of the invention.
[0007] Thus, the invention provides in a first aspect a polypeptide, wherein the polypeptide comprises or consists of an EGF-like domain (EGFLD1) selected from the group consisting of SEQ ID NO: 140-146 (i.e. SEQ ID NO: 140, 141, 142, 143, 144, 145 and 146), wherein said EGF-like domain may comprise up to five single amino acid deletions, insertions and/or mutations and wherein said EGF-like domain optionally comprises up to 30 additional amino acids at its C- and/or N-terminus.
[0008] Also provided as a second aspect is a pharmaceutical composition comprising a polypeptide of the invention.
[0009] A further aspect of the invention relates to a polypeptide of the invention for use in the prophylaxis or treatment of a neurological condition.
[0010] Also provided is the use of soluble neuregulin isoform as described herein, of a polypeptide according to the invention or of a polynucleotide encoding said polypeptide for inducing differentiation of a cell.
[0011] On the basis of the experimental evidence provided in the examples below, it is a further aspect of the invention to provide a method for producing dopaminergic neurons comprising the step of
[0012] a) contacting a non-neuronal cell with a neuregulin isoform of the invention and/or with a polypeptide of the invention.
[0013] A further aspect of the invention is an antibody capable of specifically binding to a protein selected from the group consisting of 14-3-3-zeta (SEQ ID NOs:58, 133), 14-3-3-epsilon (SEQ ID NOs:59, 134), N-ethylmaleimide sensitive factor (SEQ ID NOs:50, 124), Aldolase A, fructose-bisphosphate (SEQ ID NOs:2, 68); Aldolase C, fructose-bisphosphate (SEQ ID NO:3, 69); Triosephosphate isomerase 1 (SEQ ID NOs:4, 65, 70); similar to Glyceraldehyde-3-phosphate dehydrogenaseisoform 1 (SEQ ID NOs:5, 71, 72); Enolase 1, alpha non-neuron (SEQ ID NOs:6, 73); Enolase 2, gamma neuronal (SEQ ID NOs:7, 74); Lactate dehydrogenase B (SEQ ID NOs:8, 75); Glycerol phosphate dehydrogenase 2, mitochondrial (SEQ ID NOs:9, 76, 77); Glutamate-ammonia ligase (Glutamine synthetase) (SEQ ID NOs:10, 78, 79); Dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase complex) (SEQ ID NOs:11, 80, 66); Isocitrate dehydrogenase 3 (NAD+) alpha, isoform CRA_e (SEQ ID NOs:12, 81); Malate dehydrogenase, cytoplasmic (SEQ ID NOs:13, 82); NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8 (SEQ ID NOs:14, 83); NADH dehydrogenase (ubiquinone) Fe-S protein 1 (SEQ ID NOs:15, 84, 67); NADH dehydrogenase (ubiquinone) Fe-S protein 8 (SEQ ID NOs:16, 85); Ubiquinol-cytocrome-c reductase complex core protein 1 (SEQ ID NOs:17, 86); ATP synthase, H+ transporting, mitochondrial F0 complex, subunit d (SEQ ID NOs:18, 87, 88); Creatine kinase, brain (SEQ ID NOs:19, 89); Heat shock protein 8 (SEQ ID NOs:20, 90, 91); Heat shock protein 9 (SEQ ID NOs:21, 92); Hsp70 homolog perinuclear form (mortalin mot-2) (SEQ ID NO:22); Protein disulfide isomerase associated 3 (SEQ ID NOs:23, 93); ATPase, H+ transporting, lysosomal V1 subunit A (SEQ ID NOs:24, 94); Proteasome 26S subunit, ATPase, 4 (SEQ ID NOs:25, 95, 96); Proteasome subunit alpha type-2 (SEQ ID NOs:26, 97); Ubiquitin carboxy-terminal hydrolase L1, isoform CRA_b (SEQ ID NOs:27, 98); Valosin containing protein, isoform CRA_b (SEQ ID NOs:28, 99); 3-Hydroxyisobutyrate dehydrogenase (SEQ ID NOs:29, 100); Biphenyl hydrolast-like (SEQ ID NOs:30, 101); Haloacid dehalogenase-like hydrolast domain containing 2 (SEQ ID NOs:31, 102); Beta-actin (aa 27-375) (SEQ ID NOs:32, 103); Gamma-actin (SEQ ID NOs:33, 104); Profilin 2, isoform CRA_b (SEQ ID NOs:34, 105, 106); Transgelin 3 (SEQ ID NOs:35, 107); Annexin A6, isoform CRA_b (SEQ ID NOs:36, 108, 109); Internexin neuronal intermediate filament protein, alpha (SEQ ID NOs:37, 110); Neurofilament, light polypeptide (SEQ ID NOs:38, 111); Glial fibrillary acidic protein (SEQ ID NOs:39, 112, 113); Tubulin, alpha 1B (SEQ ID NOs:40, 114); Tubulin, beta (SEQ ID NOs:41, 115); Tubulin, beta 3 (SEQ ID NOs:42, 116); Dihydropyrimidinase-like 2 (SEQ ID NOs:43, 117); Dihydropyrimidinase-like 4, isoform CRA_c (SEQ ID NOs:44, 118); Brain abundant, membrane attached signal protein 1 (SEQ ID NOs:45, 119); RAB1B, member RAS oncogene family; isoform CRA_a (SEQ ID NOs:46, 120); RAB3A, member RAS oncogene family (SEQ ID NOs:47, 121); RAB6A, member RAS oncogene family (SEQ ID NOs:48, 122); Guanosine diphosphate dissociation inhibitor 1 (SEQ ID NOs:49, 123); Phospholiphase C-alpha (SEQ ID NOs:51, 125); Calcineurin B, type 1 (SEQ ID NOs:52, 126, 127); Calbindin-28K (SEQ ID NOs:53, 128); Calretinin (SEQ ID NOs:54, 129); Visinin-like 1 (SEQ ID NOs:55, 130); Chloride intracellular channel 4 (mitochondrial) (SEQ ID NOs:56, 131); mCG7191 (Raf Kinase Inhibitor Protein (RKIP)) (SEQ ID NOs:57, 132); Peroxiredoxin 1 (SEQ ID NOs:60, 135); Peroxiredoxin 3 (SEQ ID NOs:61, 136); Pyridoxal (pyridoxine, vitamin B6) kinase (SEQ ID NOs:62, 137); and Guanine nucleotide binding protein, alpha o isoform B (SEQ ID NOs:63, 138, 139).
[0014] for the use in diagnosing a disease.
[0015] As a further aspect the invention provides a method of diagnosing a disease comprising
[0016] (i) determining in vitro in an isolated tissue explant or an isolated body fluid of a subject the quantity of a protein having at least 90% amino acid sequence identity over its entire length with a protein selected from the group consisting of 14-3-3-zeta (SEQ ID NOs:58, 133), 14-3-3-epsilon (SEQ ID NOs:59, 134), N-ethylmaleimide sensitive factor (SEQ ID NOs:50, 124), Aldolase A, fructose-bisphosphate (SEQ ID NOs:2, 68); Aldolase C, fructose-bisphosphate (SEQ ID NOs:3, 69); Triosephosphate isomerase 1 (SEQ ID NOs:4, 65, 70); similar to Glyceraldehyde-3-phosphate dehydrogenaseisoform 1 (SEQ ID NOs:5, 71, 72); Enolase 1, alpha non-neuron (SEQ ID NOs:6, 73); Enolase 2, gamma neuronal (SEQ ID NOs:7, 74); Lactate dehydrogenase B (SEQ ID NOs:8, 75); Glycerol phosphate dehydrogenase 2, mitochondrial (SEQ ID NOs:9, 76, 77); Glutamate-ammonia ligase (Glutamine synthetase) (SEQ ID NOs:10, 78, 79); Dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase complex) (SEQ ID NOs:11, 80, 66); Isocitrate dehydrogenase 3 (NAD+) alpha, isoform CRA_e (SEQ ID NOs:12, 81); Malate dehydrogenase, cytoplasmic (SEQ ID NOs:13, 82); NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8 (SEQ ID NOs:14, 83); NADH dehydrogenase (ubiquinone) Fe-S protein 1 (SEQ ID NOs:15, 84, 67); NADH dehydrogenase (ubiquinone) Fe-S protein 8 (SEQ ID NOs:16, 85); Ubiquinol-cytochrome-c reductase complex core protein 1 (SEQ ID NOs:17, 86); ATP synthase, H+ transporting, mitochondral F0 complex, subunit d (SEQ ID NOs:18, 87, 88); Creatine kinase, brain (SEQ ID NOs:19, 89); Heat shock protein 8 (SEQ ID NOs:20, 90, 91); Heat shock protein 9 (SEQ ID NOs:21, 92); Hsp70 homolog perinuclear form (mortalin mot-2) (SEQ ID NO:22); Protein disulfide isomerase associated 3 (SEQ ID NOs:23, 93); ATPase, H+ transporting, lysosomal V1 subunit A (SEQ ID NOs:24, 94); Proteasome 26S subunit, ATPase, 4 (SEQ ID NOs:25, 95, 96); Proteasome subunit alpha type-2 (SEQ ID NOs:26, 97); Ubiquitin carboxy-terminal hydrolase L1, isoform CRA_b (SEQ ID NOs:27, 98); Valosin containing protein, isoform CRA_b (SEQ ID NOs:28, 99); 3-Hydroxyisobutyrate dehydrogenase (SEQ ID NOs:29, 100); Biphenyl hydrolase-like (SEQ ID NOs:30, 101); Haloacid dehalogenase-like hydrolase domain containing 2 (SEQ ID NOs:31, 102); Beta-actin (aa 27-375) (SEQ ID NOs:32, 103); Gamma-actin (SEQ ID NOs:33, 104); Profilin 2, isoform CRA_b (SEQ ID NOs:34, 105, 106); Transgelin 3 (SEQ ID NOs:35, 107); Annexin A6, isoform CRA_b (SEQ ID NOs:36, 108, 109); Internexin neuronal intermediate filament protein, alpha (SEQ ID NOs:37, 110); Neurofilament, light polypeptide (SEQ ID NOs:38, 111); Glial fibrillary acidic protein (SEQ ID NOs:39, 112, 113); Tubulin, alpha 1B (SEQ ID NOs:40, 114); Tubulin, beta (SEQ ID NOs:41, 115); Tubulin, beta 3 (SEQ ID NOs:42, 116); Dihydropyrimidinase-like 2 (SEQ ID NOs:43, 117); Dihydropyrimidinase-like 4, isoform CRA_c (SEQ ID NOs:44, 118); Brain abundant, membrane attached signal protein 1 (SEQ ID NOs:45, 119); RAB1B, member RAS oncogene family; isoform CRA_a (SEQ ID NOs:46, 120); RAB3A, member RAS oncogene family (SEQ ID NOs:47, 121); RAB6A, member RAS oncogene family (SEQ ID NOs:48, 122); Guanosine diphosphate dissociation inhibitor 1 (SEQ ID NOs:49, 123); Phospholipase C-alpha (SEQ ID NOs:51, 125); Calcineurin B, type I (SEQ ID NOs:52, 126, 127); Calbindin-28K (SEQ ID NOs:53, 128); Calretinin (SEQ ID NOs:54, 129); Visinin-like 1(SEQ ID NOs:55, 130); Chloride intracellular channel 4 (mitochondrial) (SEQ ID NOs:56, 131); mCG7191 (Raf Kinase Inhibitor Protein (RKIP)) (SEQ ID NOs:57, 132); Peroxiredoxin 1 (SEQ ID NOs:60, 135); Peroxiredoxin 3 (SEQ ID NOs:61, 136); Pyridoxal (pyridoxine, vitamin B6) kinase (SEQ ID NOs:62, 137); and Guanine nucleotide binding protein, alpha o isoform B (SEQ ID NOs:63, 138, 139) or a polynucleotide encoding said protein; and
[0017] (ii) optionally determining whether the amount of protein differs from the amount of the corresponding protein quantified in a healthy subject; and
[0018] (iii) optionally correlating a changed expression of said protein with a neurological disease.
[0019] In a further aspect the invention also provides a polynucleotide encoding a polypeptide of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0020] Before the present invention is described is detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.
[0021] Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H. G. W. Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland) and as described in "Pharmaceutical Substances: Syntheses, Patents, Applications" by Axel Kleemann and Jurgen Engel, Thieme Medical Publishing, 1999; the "Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals", edited by Susan Budavari et al., CRC Press, 1996, and the United States Pharmacopeia-25/National Formulary-20, published by the United States Pharmcopeial Convention, Inc., Rockville Md., 2001.
[0022] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated feature, integer or step or group of features, integers or steps but not the exclusion of any other feature, integer or step or group of integers or steps. In the following passages different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.
[0023] Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions, etc.), whether supra or infra, are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
[0024] In part, the present invention is based on the surprising finding that a soluble neuregulin-1 isoform, e.g. Nrg1β1-ECD as described herein, is capable of providing neuroprotection of, e.g., dopaminergic neurons and/or inducing differentiation of, e.g., erbB4- and/or erB3-expressing cells that do not express neuromelanin and tyrosine hydroxylase and/or non-neuronal cells, such as glial cells, particularly astrocytes, oligondentrocytes, ependymal cells, radio glial cells, Schwann cells, satellite cells and/or enteric glia cells in, e.g., dopaminergic neurons. In the case of differentiation of such cells in dopaminergic neurons, the increase in such neurons will increase the endogenous dopamine production. Such an increase in endogenous dopamine and/or the neuroprotective effect of neuregulin-1 are particularly useful for the symptomatic relief of patients suffering from Parkinson'disease. Without being bound to any theory, the inventors of the present invention believe that the new curative effect of neuregulin-1, i.e., neuroprotection and/or neuronal differentiation, is effected by the induction of tyrosine hydroxylase in non-neuronal cells, preferably erbB4- or erbB3-expressing cells. It is further believed that the duality of neuroprotection and induction of neuronal differentiation is the key for a new therapy, e.g., healing, for Parkinson's disease.
[0025] Furthermore, the present invention is based on the unexpected finding as deduced from in silico experiments that (i) small fragments of the extracellular domain of neuregulin are sufficient to bind erbB4- or erbB3-receptors and that (ii) polypeptides comprising multiple copies of selected domains of the neuregulin protein as described herein below, e.g. of neuregulin-1 protein show not only an increased binding affinity to the erbB4- or erbB3-receptors but also an enrichment near cells which naturally express erbB4- or erbB3-receptors. These improved polypeptides of the invention can thus be administered in smaller amounts to a subject such as a human patient and still be pharmaceutically effective, i.e. still have the same therapeutic effect as a polypeptide of the prior art that is administered at a larger dose. Smaller dosage forms are not only cheaper to produce but also provide the advantage that possible side-effects can be minimized as the therapeutic polypeptides specifically accumulate at the target cells and bind there with improved affinity to the mentioned receptors.
[0026] The present invention also provides a soluble neuregulin-1 isoform or a nucleic acid molecule encoding a soluble neuregulin-1 isoform all as described herein for the prevention, amelioration and/or treatment of a neurological disorder by induction of neuronal differentiation and/or neuroprotection. In a preferred embodiment, a neurological disorder is selected from the group consisting of schizophrenia, in particular cognition-related aspects of schizophrenia; Parkinson's disease; Alzheimer'disease; Multiple Sclerosis (MS); Amyotrophic Lateral Sclerosis (ALS); epilepsy; stroke; traumatic brain injury; spinal chord injury; bipolar disorders; depression; frontotemporal dementia; seizures; ischemia; neuropathy, particulary diabetic neuropathy; neuralgia; neuropathic pain; and inclusion-body myopathy. In a particulary preferred embodiment the neurological disorder is Parkinson's disease or bipolar disorder.
[0027] The present invention further provides a soluble neuregulin-1 isoform or a nucleic acid molecule encoding a soluble neuregulin-1 isoform all as described herein for the prevention, amelioration and/or treatment of a disorder associated with a loss of neurons, such as a neurological disorder, e.g., a neurological disorder selected from the group consisting of schizophrenia, in particular cognition-related aspects of schizophrenia; Parkinson's disease; Alzheimer's disease; Multiple Sclerosis (MS); Amyotrophic Lateral Sclerosis (ALS); epilepsy; stroke; traumatic brain injury; spinal chord injury; bipolar disorders; depression; frontotemporal dementia; seizures; ischemia; neuropathy, particulary diabetic neuropathy; neuralgia; neuropathic pain; and inclusion-body myopathy. In a particularly preferred embodiment the loss of neurons is associated with the neurological disorder Parkinson's disease, in a further preferred embodiment the loss of neurons is prevented by induction of neuronal differentiation and/or neuroprotection as described herein. In a preferred embodiment of the invention, the loss of neurons is the result of excitotoxicity, preferably glutamate-induced excitotoxicity as described in Schrattenholz et al, 2006, Current Topics in Medical Chemistry 6, 663-586.
[0028] In a further preferred embodiment of the invention, the neuronal differentiation as described herein is induced in erbB4- and/or erbB3-expressing cells that do not express neuromelanin and tyrosine hydroxylase and/or non-neuronal cells, such as glial cells, particulary astrocytes, oligondentrocytes, ependymal cells, radio glial cells, Schwann cells, satellite cells and/or enteric glia cells.
[0029] In a further embodiment of the invention, the neuronal differentiation is induced by altering the expression level of one or more proteins of Table 2 as described herein, e.g., of Aldolase A, fructose-bisphosphate (SEQ ID NOs:2, 68); Aldolase C, fructose-bisphosphate (SEQ ID NOs:3, 69); Triosephosphate isomerase 1 (SEQ ID NOs:4, 65, 70); similar to Glyceraldehyde-3-phosphate dehydrogenaseisoform 1 (SEQ ID NOs:5, 71, 72); Enolase 1, alpha non-neuron (SEQ ID NOs:6, 73); Enolase 2, gamma neuronal (SEQ ID NOs:7, 74); Lactate dehydrogenase B (SEQ ID NOs:8, 75); Glycerol phosphate dehydrogenase 2, mitochondrial (SEQ ID NOs:9, 76, 77); Glutamate-ammonia ammonia ligase (Glutamine synthetase) (SEQ ID NOs:10, 78, 79); Dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase complex) (SEQ ID NOs:11, 80,66); Isocitrate dehydrogenase 3 (NAD+) alpha, isoform CRA_e (SEQ ID NOs:12, 81); Malate dehydrogenase, cytoplasmic (SEQ ID NOs:13, 82); NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8 (SEQ ID NOs:14, 83); NADH dehydrogenase (ubiquinone) Fe-S protein 1 (SEQ ID NOs:15, 84, 67); NADH dehydrogenase (ubiquinone) Fe-S protein 8 (SEQ ID NOs:16, 85); Ubiquinol-cytochrome-e reductase complex core protein 1 (SEQ ID NOs:17, 86); ATP synthase, H+ transporting, mitochondrial F0 complex, subunit d (SEQ ID NOs:18, 87, 88); Creatine kinase, brain (SEQ ID NOs:19, 89); Heat shock protein 8 (SEQ ID NOs:20, 90, 91); Heat shock protein 9 (SEQ ID NOs:21, 92); Hsp70 homolog perinuclear form (mortalin mot-2) (SEQ ID NO:22); Protein disulfide isomerase associated 3 (SEQ ID NOs:23, 93); ATPase, H+ transporting, lysosomal V1 subunit A (SEQ ID NOs:24, 94); Proteasome 268 subunit, ATPase, 4 (SEQ ID NOs:25, 95, 96); Proteasome subunit alpha type-2 (SEQ ID NOs:26, 97); Ubiquitin carboxy-terminal hydrolase L1, isoform CRA_b (SEQ ID NOs:27, 98); Valosin containing protein, isoform CRA_b (SEQ ID NOs:28, 99); 3-Hydroxyisobutyrate dehydrogenase (SEQ ID NOs:29, 100); Biphenyl hydrolase-like (SEQ ID NOs:30, 101); Haloacid dehalogenase-like hydrolase domain containing 2 (SEQ ID NOs:31, 102); Beta-actin (aa 27-375) (SEQ ID NOs:32, 103); Gamma-actin (SEQ ID NOs:33, 104); Profilin 2, isoform CRA_b (SEQ ID NOs:34, 105, 106); Transgelin 3 (SEQ ID NOs:35, 107); Annexin A6, isoform CRA_b (SEQ ID NOs:36, 108, 109); Internexin neuronal intermediate filament protein, alpha (SEQ ID NOs:37, 110); Neurofilament, light polypeptide (SEQ ID NOs:38, 111); Glial fibrillary acidic protein (SEQ ID NOs:39, 112, 113); Tubulin alpha 1B (SEQ ID NOs:40, 114); Tubulin, beta (SEQ ID NOs:41, 115); Tubulin, beta 3 (SEQ ID NOs:42, 116); Dihydropyrimidinase-like 2 (SEQ ID NOs:43, 117); Dihydropyrimidinase-like 4, isoform CRA_c (SEQ ID NOs:44, 118); Brain abundant, membrane attached signal protein 1 (SEQ ID NOs:45, 119); RAB1B, member RAS oncogene family; isoform CRA_a (SEQ ID NOs:46, 120); RAB3A, member RAS oncogene family (SEQ ID NOs:47, 121); RAB6A, member RAS oncogene family (SEQ ID NOs:48, 122); Guanosine diphosphate dissociation inhibitor 1 (SEQ ID NOs:49, 123); Phospholipase C-alpha (SEQ ID NOs:51, 125); Calcineurin B, type 1 (SEQ ID NOs:52, 126, 127); Calbindin-28K (SEQ ID NOs:53, 128); Calretinin (SEQ ID NOs:54, 129); Visinin-like 1 (SEQ ID NOs:55, 130); Chloride intracellular channel 4 (mitochondrial) (SEQ ID NOs:56, 131); mCG7191 (Raf Kinase Inhibitor Protein (RKIP)) (SEQ ID NOs:57, 132); Peroxiredoxin 1 (SEQ ID NOs:60, 135); Peroxiredoxin 3 (SEQ ID NOs:61, 136); Pyridoxal (pyridoxine, vitamin B6) kinase (SEQ ID NOs:62, 137); Gunanine nucleotide binding protein, alpha o isoform B (SEQ ID NOs:63, 138, 139); 14-3-3-zeta (SEQ ID NOs:58, 133); 14-3-3-epsilon (SEQ ID NOs:59, 134); and N- ethylmalcimide sensitive factor (SEQ ID NOs:50, 124).
[0030] In one embodiment, the alteration of the expression level is a decrease in expression of a protein of Table 2 as described herein and as selected from the group consisting of 14-3-3-zeta (SEQ ID NOs:58, 133), 14-3-3-epsilon (SEQ ID NOs:59, 134), and N-ethylmaleimide sensitive factor (SEQ ID NOs:50, 124).
[0031] In another embodiment, the alteration of the expression level is an increase in expression of a protein of Table 2 as described herein and as selected from the group consisting of Aldolase A, fructose-bisphosphate (SEQ ID NOs:2, 68); Aldolase C, fructose-bisphosphate (SEQ ID NOs:3, 69); Triosephosphate isomerase 1 (SEQ ID NOs:4, 65, 70); similar to Glyceraldehyde-3-phosphate dehydrogenaseisoform 1 (SEQ ID NOs:5, 71, 72); Enolase 1, alpha non-neuron (SEQ ID NOs:6, 73); Enolase 2, gamma neuronal (SEQ ID NOs:7, 74); Lactate dehydrogenase B (SEQ ID NOs:8, 75); Glycerol phosphate dehydrogenase 2, mitochondrial (SEQ ID NOs:9, 76, 77); Glutamate-ammonia ligase (Glutamine synthetase) (SEQ ID NOs:10, 78, 79); Dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase complex) (SEQ ID NOs:11, 80, 66); Isocitrate dehydrogenase 3 (NAD+) alpha, isoform CRA_e (SEQ ID NOs:12, 81); Malate dehydrogenase, cytoplasmic (SEQ ID NOs:13, 82); NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8 (SEQ ID NOs:14, 83); NADH dehydrogenase (ubiquinone) Fe-S protein 1 (SEQ ID NOs:15, 84, 67); NADH dehydrogenase (ubiquinone) Fe-S protein 8 (SEQ ID NOs:16, 85); Ubiquinol-cytochrome-e reductase complex core protein 1 (SEQ ID NOs:17, 86); ATP synthase, H+ transporting, mitochondrial F0 complex, subunit d (SEQ ID NOs:18, 87, 88); Creatine kinase, brain (SEQ ID NOs:19, 89); Heat shock protein 8 (SEQ ID NOs:20, 90, 91); Heat shock protein 9 (SEQ ID NOs:21, 92); Hsp70 homolog perinuclear form (mortalin mot-2) (SEQ ID NO:22); Protein disulfide isomerase associated 3 (SEQ ID NOs:23, 93); ATPase, H+ transporting, lysosomal V1 subunit A (SEQ ID NOs:24, 94); Proteasome 268 subunit, ATPase, 4 (SEQ ID NOs:25, 95, 96); Proteasome subunit alpha type-2 (SEQ ID NOs:26, 97); Ubiquitin carboxy-terminal hydrolase L1, isoform CRA_b (SEQ ID NOs:27, 98); Valosin containing protein, isoform CRA_b (SEQ ID NOs:28, 99); 3-Hydroxyisobutyrate dehydrogenase (SEQ ID NOs:29, 100); Biphenyl hydrolase-like (SEQ ID NOs:30, 101); Haloacid dehalogenase-like hydrolase domain containing 2 (SEQ ID NOs:31, 102); Beta-actin (aa 27-375) (SEQ ID NOs:32, 103); Gamma-actin (SEQ ID NOs:33, 104); Profilin 2, isoform CRA_b (SEQ ID NOs:34, 105, 106); Transgelin 3 (SEQ ID NOs:35, 107): Annexin A6, isoform CRA_b (SEQ ID NOs:36, 108, 109); Internexin neuronal intermediate filament protein, alpha (SEQ ID NOs:37, 110); Neurofilament, light polypeptide (SEQ ID NOs: 38, 111); Glial fibrillary acidic protein (SEQ ID NOs:39, 112, 113); Tubulin, alpha 1B (SEQ ID NOs:40, 114); Tubulin, beta (SEQ ID NOs:41, 115); Tubulin, beta 3 (SEQ ID NOs:42, 116); Dihydropyrimidianse-like 2 (SEQ ID NOs:43, 117); Dihydropyrimidinase-like 4, isoform CRA_c (SEQ ID NOs:44, 118); Brain abundant, membrane attached signal protein 1 (SEQ ID NOs:45, 119); RAB1B, member RAS oncogene family, isoform CRA_a (SEQ ID NOs:46, 120); RAB3A, member RAS oncogene family (SEQ ID NOs:47, 121); RAB6A, member RAS oncogene family (SEQ ID NOs:48, 122); Guanosine diphosphate dissociation inhibitor 1 (SEQ ID NOs:49, 123); Phospholipase C-alpha (SEQ ID NOs:51, 125); Calcineurin B, type 1 (SEQ ID NOs:52, 126, 127); Calbindin-28K (SEQ ID NOs:53, 128); Calretinin (SEQ ID NOs:54, 129); Visinin-like 1(SEQ ID NOs:55, 130); Chloride intracellular channel 4 (mitochondrial) (SEQ ID NOs:56, 131); mCG7191 (Raf Kinase Inhibitor Protein (RKIP)) (SEQ ID NOs:57, 132); Peroxiredoxin 1 (SEQ ID NOs:60, 135); Peroxiredoxin 3 (SEQ ID NOs:61, 136); Pyridoxal (pyridoxine, vitamin B6) kinase (SEQ ID NOs:62, 137); and Guanine nucleotide binding protein, alpha o isoform B (SEQ ID NOs:63, 138, 139). Particularly preferred is the alteration of the expression level that is an increase in expression of the protein Dihydropyrimidinase-like 2 (SEQ ID NOs:43, 117). Particularly, preferred is the alteration of the expression level that is an increase in expression of the protein Valosin containing protein, isoform_b (SEQ ID NO:28, 99).
[0032] The term "a protein of Table 2" as used throughout the application refers to a mammalian protein, most preferably a mouse, a rat or a human protein. The term "protein of Table 2" as used herein also includes variants of these proteins such as allelic variants, splice variants or variants, particularly human variants with 99%, 98%; 97%, 96%, 95%, 93%, 90%, 85% or 80% identity to the mouse proteins described herein, e.g. the mouse protein referred to in Table 2 as well as derivatives functionally active or fragments of these proteins. The term "% identity" as used in the above context and also as used generally throughout this specification refers to the %-identity that is identified on the basis of the BLAST program (Altschul, S. F., Gish, W., Miller, W., Myers, E. W. & Lipman, D. J. (1990) "Basic local alignment search tool." J. Mol. Biol. 215:403-410; Gish, W. & States, D. J. (1993) "Identification of protein coding regions by database similarity search." Nature Genet. 3:266-272; Madden, T. L., Tatusov, R. L. & Zhang, J. (1996) "Applications of network BLAST server" Meth. Enzymol. 266:131-141: Altschul, S. F., Madden T. L., Schaffer, A. A., Zhang, J., Zhang, Z., Miller, W. & Lipman, D. J. (1997) "Gapped BLAST and PSI-BLAST: a new generation of protein database search programs." Nucleic Acids Res. 25:3389-3402) by using the database RefSeq protein. In one preferred embodiment the percent identity is determined with respect to the sequence which is longest, i.e. the longer of the two sequences which are compared to each other is preferably the reference sequence. The proteins of Table 2 may be used for the prevention, amelioration and/or treatment of the neurological disorder. Proteins of Table 2 that may be used in the context of the invention are selected from the group consisting of Aldolase A, fructose-bisphosphate (SEQ ID NOs:2, 68); Aldolase C, fructose-bisphosphate (SEQ ID NO:3, 69); Triosephosphate isomerase 1 (SEQ ID NOs:4, 65, 70); similar to Glyceraldehyde-3-phosphate Dehydrogenaseisoform 1 (SEQ ID NOs:5, 71, 72); Enolase 1, alpha non-neuron (SEQ ID NOs:6, 73); Enolase 2, gamma neuronal (SEQ ID NOs:7, 74); Lactate dehydrogenase B (SEQ ID NOs:8, 75); Glycerol phosphate dehydrogenase 2, mitochondrial (SEQ ID NOs:9, 76, 77); Glutamate-ammonia ligase (Glutamine synthetase (SEQ ID NOs:10, 78, 79); Dihydrolipoamide S- acetyltransferase (E2 component of pyrovate dehydrogenase complex) (SEQ ID NOs:11, 80, 66); Isocitrate dehydrogenase 3 (NAD+) alpha, isoform CRA_e (SEQ ID NOs:12, 81); Malate dehydrogenase, cytoplasmic (SEQ ID NOs:13, 82); NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8 (SEQ ID NOs:14, 83); NADH dehydrogenase (ubiquinone) Fe-S protein 1 (SEQ ID NOs:15, 84, 67); NADH dehydrogenase (ubiquinone) Fe-S protein 8 (SEQ ID NOs:16, 85); Ubiquinol-cytochrome-c reductase complex core protein 1 (SEQ ID NOs:17, 86); ATP synthase, H+ transporting, mitochondrial F0 complex, subunit d (SEQ ID NOs:18, 87, 88); Creatine kinase, brain (SEQ ID NOs:19, 89); Heat shock protein 8 (SEQ ID NOs:20, 90, 91); Heat shock protein 9 (SEQ ID NOs:21, 92); Hsp70 homolog perinuclear form (mortalin mot-2) (SEQ ID NO:22); Protein disulfide isomerase associated 3 (SEQ ID NOs:23, 93); ATPase, H+ transporting, lysosomal V1 subunit A (SEQ ID NOs:24, 94); Proteasome 26S subunit, ATPase, 4 (SEQ ID NOs:25, 95, 96); Proteasome subunit alpha type-2 (SEQ ID NOs:26, 97); Ubiquitin carboxy-terminal hydrolase L1, isoform CRA_b (SEQ ID NOs:27, 98); Valosin containing protein, isoform CRA_b (SEQ ID NOs:28, 99); 3-Hydroxyisobutyrate dehydrogenase (SEQ ID NOs:29, 100); Biphenyl hydrolase-like (SEQ ID NOs:30, 101); Haloacid dehalogenase-like hydrolase domain containing 2 ((SEQ ID NOs:31, 102); Beta-actin (aa 27-375) (SEQ ID NOs:32, 103); Gamma-actin (SEQ ID NOs:33, 104); Profilin 2, isoform CRA_b (SEQ ID NOs:34, 105, 106); Transgelin 3 (SEQ ID NOs:35, 107); Annexin A6, isoform CRA_b (SEQ ID NOs:36, 108, 109); Internexin neuronal intermediate filament protein, alpha (SEQ ID NOs:37, 110); Neurofilament, light polypeptide (SEQ ID NOs:38, 111); Glial fibrillary acidic protein (SEQ ID NOs:39, 112, 113); Tubulin, alpha 1B (SEQ ID NOs:40, 114); Tubulin, beta (SEQ ID NOs:41, 115); Tubulin, beta 3 (SEQ ID NOs:42, 116); Dihydropyrimidinase-like 2 (SEQ ID NOs:43, 117); Dihydropyrimidinase-like 4, isoform CRA_c (SEQ ID NOs:44, 118); Brain abundant, membrane attached signal protein 1 (SEQ ID NOs:45, 119); RAB1B, member RAS oncogene family; isoform CRA_a (SEQ ID NOs:46, 120); RAB3A, member RAS oncogene family (SEQ ID NOs:47, 121); RAB6A, member RAS oncogene family (SEQ ID NOs:48, 122); Guanosine diphosphate dissociation inhibitor 1 (SEQ ID NOs:49, 123); Phospholipase C-alpha (SEQ ID NOs:51, 125); Calcineurin B, type 1 (SEQ ID NOs:52, 126, 127); Calbindin-28K (SEQ ID NOs:53, 128); Calretinin (SEQ ID NOs:54, 129); Visinin-like 1 (SEQ ID NOs:55, 130); Chloride intracellular channel 4 (mitochondrial) (SEQ ID NOs:56, 131); mCG7191 (Raf Kinase Inhibitor Protein (RKIP)) (SEQ ID NOs:57, 132); Peroxiredoxin 1 (SEQ ID NOs:60, 135); Peroxiredoxin 3 (SEQ ID NOs:61, 136); Pyridoxal (pyridoxine, vitamin B6) kinase (SEQ ID NOs:62, 137); Guanine nucleotide binding protein, alpha o isoform B (SEQ ID NOs:63, 138, 139); 14-3-3-zeta (SEQ ID NOs:58, 133); 14-3-3-epsilon (SEQ ID NOs:59, 134); and N-ethylmaleimide sensitive factor (SEQ ID NOs:50, 124). Particularly preferred is the neuronal differentiation that is induced by increasing the expression level of Dihydropyrimidinase-like 2 (SEQ ID NO: 43, 117). Particularly preferred is also the neuronal differentiation that is induced by increasing the expression level of Valosin containing protein, isoform CRA_b (SEQ ID NOs:28, 99). Alternatively, the neuronal differentiation is preferred that is induced by decreasing the expression level of 14-3-3-zeta (SEQ ID NOs:,58, 133), 14-3-3-epsilon (SEQ ID NOs: 59, 134) and/or N-ethylmaleimide sensitive factor (SEQ ID NOs: 50, 124).
[0033] The invention further relates to a soluble neuregulin-1 isoform which is preferably a human neuregulin-1 isoform, e.g., a recombinant isoform comprising the primary amino acid sequence of a naturally occurring human neuregulin-1 isoform or a sequence which has a identity of at least 90%, preferably at least 95% and most preferably of at least 98% based on the total length of the recombinant isoform.
[0034] The invention also includes of a soluble neuregulin-1 isoform such as allelic variants or splice variants as well as derivatives or fragments of these proteins. Preferably, said derivative is a glycosylated form of the protein.
[0035] The soluble neuregulin-1 isoform may be a neuregulin-1 Type I, Type II, Type III, Type IV, Type V or Type VI isoform, preferably a neuregulin-1β1 isoform, a neuregulin-1 α isoform or a Sensory and motor neuron-derived factor (SMDF) isoform, particularly a neuregulin-1β1 isoform and more particularly a human neuregulin-1β1 isoform.
[0036] In a preferred embodiment, the soluble neuregulin-1 isoform is characterized in that it passes the blood brain barrier, e.g., a neuregulin-1β1 isoform.
[0037] The soluble neuregulin-1 isoform comprises at least a portion of the extracellular domain of neuregulin-1 or fragments thereof, particularly the EGF-like domain or the EGF-like domain, the IgG-like domain and the heparin sulfate binding motif, particularly an isoform that comprises or is SEQ ID NO:1. In a preferred embodiment, the soluble neuregulin-1 isoform comprises:
[0038] (a) nucleotides 46-634 of SEQ ID NO:64,
[0039] (b) amino acids 176-246 of SEQ ID NO:1, and/or
[0040] (c) amino acids 2-246 of SEQ ID NO:1 (also described as NRG-β1-ECD herein).
[0041] In a preferred embodiment of the polypeptide of the invention described herein below, the polypeptide comprises:
[0042] (a) a polypeptide encloded by nucelotides 46-634 of SEQ ID NO:64,
[0043] (b) a polypeptide consisting of amino acids 176-246 of SEQ ID NO:1, and/or
[0044] (c) a polypeptide consisting of amino acids 2-246 of SEQ ID NO:1, wherein the polypeptide in (a), (b) and (c) may comprise up to 13 single amino acid deletions, insertions and/or mutations.
[0045] In a particularly preferred embodiment, the soluble neuregulin-1 isoform comprises amino acids 2-246 of SEQ ID NO:1.
[0046] The invention also provides a nucleic acid molecule encoding a soluble neuregulin-1 isoform as described herein, preferably a nucleic acid molecule comprising SEQ ID NO: 64, or encoding a protein of Table 2 as described herein as well as a vector comprising such a nucleic acid molecule, e.g., an expression vector. The nucleic acid molecule or the vector all as described herein may be transfected into a cell, which may be a prokaryotic cell, e.g. an E. coli cell, or an eukaryotic cell.
[0047] In one embodiment of the invention, the nucleic acid molecule encoding the soluble neuregulin-1 isoform of the nucleic acid molecule encoding a protein of Table 2 all as described herein is for the therapeutic uses as described herein, e.g., for the prevention, amelioration and/or treatment of a neurological disorder by induction of neuronal differentiation and/or neuroprotection as described herein or for the prevention, amelioration and/or treatment of a disorder associated with a loss of neurons as described herein, preferably for the prevention, amelioration and/or treatment of Parkinson's disease.
[0048] The invention further relates to the soluble neuregulin-1 isoform, a nucleic acid molecule encoding a soluble neuregulin-1 isoform, the protein of table 2, or a nucleic acid molecule encoding a protein of Table 2, all as described herein, in combination with a further active agent, e.g., an agent for the treatment of neurological conditions and/or neurological disorders such as Parkinson's disease, Alzheimer's disease, Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), epilepsy, stroke, traumatic brain injury, spinal chord injury, psychotic disorders such as schizophrenia, bipolar disorders and depression, e.g. olanzapine or clozapine.
[0049] The invention further relates to a pharmaceutical composition comprising as active agent a soluble Neuregulin-1 isoform, a nucleic acid molecule encoding a soluble neuregulin-1 isoform, a protein of Table 2 or a nucleic acid molecule encoding a protein of Table2, all as described herein and optionally a pharmaceutically active carrier.
[0050] The invention further provides a method for studying a neurological disorder, the molecular mechanism of, the physiological processes associated with a loss of neurons, or a disorder associated with a loss of neurons comprising:
[0051] (a) administering a neuregulin-1 isoform preferably as described herein, to a cell or a non-human vertebrate animal;
[0052] (b) subjecting said cell or an organ or tissue sample of said to a proteome analysis or gene expression analysis; and
[0053] (c) comparing the proteome analysis or the gene expression analysis to the respective analysis of a control cell or a control non-human animal.
[0054] In the above method, the neurological disorder may be selected from the group consisting of schizophrenia, in particular cognition-related aspects of schizophrenia; Parkinson'disease; Alzheimer's disease; Multiple Sclerosis (MS); Amyotrophic Lateral Sclerosis (ALS); epilepsy; stroke; traumatic brain injury; spinal chord injury; bipolar disorders; depression; frontotemporal dementia; seizures; ischemia; neuropathy, particularly diabetic neuropathy; neuralgia; neuropathic pain; and inclusion body myopathy. In preferred embodiment, the neurological disorder is Parkinson's disease.
[0055] In the methods described herein the non-human vertebrate animal may be selected from the group consisting of mouse, rat, rabbit, hamster, bird, cat, sheep, bovine, and horse, preferably a mouse, and most preferably a mouse model for a neurological disorder, such as for Parkinson's disease, preferably by inducing neuronal death with 6-hydroxydopamine (6-OHDH) in wild-type mice or the transgenic mouse model A53T alpha-synuclein (Harvey BK, Wang Y, Hoffer BJ. Transgenic rodent models of Parkinson's disease. Acta Neurochir Suppl. 2008:101:89-92: Chesselet MF. In vivo alpha-synuclein overexpression in rodents: a useful model of Parkinson's disease? Exp Neurol. 2008 January;209(1):22-7) or for Alzheimer's disease, preferably the APP/PS mouse model (Meyer-Luchmann, M.: Coomaraswamy, J.; Bolmont, T.; Kaeser, S.; Schaefer, C.; Kilger, E.; Neuenschwander, A.; Abramowski, D.; Frey, P.; Jaton, A. L.; Vigouret, J. M.; Paganetti, P.; Walsh, D. M.; Mathews, P. M.; Ghiso, J.; Staufenbiel, M.; Walker, L. C.; Jucker, M (2006) Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host, Science 313, 1781-1784; Radde, R.; Bolmont, T.; Kaeser, S. A.; Coomaraswamy, J.; Lindau, D.; Stoltze, L.; Calhoun, M. E.; Jaggi, F.; Wolburg, H.; Gengler, S.; Haass, C.; Ghetti, B.; Czech, C.; Holscher, C.; Mathews, P. M.; Jucker, M; Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology (2006) EMBO Report 7, 940-946). Alternatively, the non-human animal model may be a wild-type animal.
[0056] The invention further provides a method for identifying and/or testing an agent that alters the expression and/or function of any one of the proteins of Table 2 or the nucleic acids encoding a protein of Table 2 comprising:
[0057] (a) administering said agent to a cell or a non-human vertebrate animal;
[0058] (b) measuring or monitoring the expression and/or function of said proteins of nucleic acid molecules encoding said proteins; and
[0059] (c) comparing the expression and/or function of said proteins or nucleic acid molecules to the expression and/or function of said proteins or nucleic acid molecules in a control cell or a control non-human vertebrate animal.
[0060] A particularly preferred protein of Table 2 in the above method is Dihydropyrimidinase-like 2 (SEQ ID NOs:43, 117) and/or Valosin containing protein, isoform CRA_b (SEQ ID NOs:28, 99). Another preferred protein of Table 2 in the above method is 14-3-3-zeta (SEQ ID NOs:58, 133), 14-3-3-epsilon (SEQ ID NOs:59, 134) and/or N-ethylmaleimide sensitive factor (SEQ ID NOs:50, 124).
[0061] The expression of said proteins is measured by differential expression analysis with, e.g., isotope markers such as radioactive or stable isotopes which lead to a differential display. Alternatively, the expression of said proteins is measured with 2D gel-electrophoresis or mass spectrometry.
[0062] The expression of said nucleic acid molecules may be measured with DNA/RNA arrays, e.g. affymetrix.
[0063] Cells that may be used is the context of the methods described herein are LUHMES cells (Schildknecht, S.; Poltl, D.; Nagel, D. M.; Matt, F.; Scholz, D.; Lotharius, J.; Schmieg, N.; Salvo-Vargas, A.; Leist, M., 2009, Requirement of a dopaminergic neuronal phenotype for toxicity of low concentrations of 1-methyl-4-phenylpyridinium to human cells. Toxicol.Applied Pharmacol 241, 23-35) or any other neuronal cell, like a neuroblstoma cell, a primary culture of a neuronal cell and in particular include SHSY5Y cells (ATCC CRL-2266).
[0064] In the above described methods, the term "control cell" and "control non-human animal" refers to a cell or an animal that is used in a parallel experiment with identical conditions except for receiving said neuregulin-1 isoform or said agent.
[0065] Also the following items are within the ambit of the present invention:
[0066] A first item concerns a soluble neuregulin-1 isoform as described herein for the prevention, amelioration and/or treatment of a neurological disorder by induction of neuronal differentiation and/or neuroprotection.
[0067] The invention provides in a second item a soluble neuregulin-1 isoform as described herein for the prevention, amelioration and/or treatment of a disorder associated with a loss of neurons.
[0068] Item 3 provides the soluble neuregulin-1 isoform of item 2, wherein the loss of neurons is the result of excitotoxicity, preferably glutamate induced excitotoxicity.
[0069] In one embodiment, the invention provides as item 4 the soluble neuregulin-1 isoform of items 2 or 3, wherein the loss of neurons is prevented by induction of neuronal differentiation and/or neuroprotection.
[0070] In a further embodiment, the invention provides as item 5 the soluble neuregulin-1 isoform of item 1 or item 4, wherein the neuronal differentiation is induced in non-neuronal cells, such as glial cells, particularly astrocytes, oligondentrocytes, ependymal cells, radio glial cells, Schwann cells, satellite cells and/or enteric glia cells.
[0071] In a further embodiment, the invention provides as item 6 the soluble neuregulin-1 isoforms of any one of items 1, 4 or 5, wherein the neuronal differentiation is induced in erbB4- and/or erbB3-expressing cells that do not express neuromelanin and tyrosine hydroxylase.
[0072] In a further embodiment, the invention provides as item 7 the soluble neuregulin-1 isoform of any one of items 1 and 4-6, wherein the neuronal differentiation is induced by altering the expression level of one or more proteins disclosed in Table 2.
[0073] In a further embodiment, the invention provides as item 8 the soluble neuregulin-1 isoform of item 7, wherein the alteration of the expression level is a decrease in expression of a protein selected from the group consisting of 14-3-3-zeta (SEQ ID NOs:58, 133), 14-3-3-epsilon (SEQ ID NOs:59, 134), and N-ethylmaleimide sensitive factor (SEQ ID NOs:50, 124).
[0074] In a further embodiment, the invention provides as item 9 the soluble neuregulin-1 isoform of item 7, wherein the alteration of the expression level is an increase in expression of a protein selected from the group consisting of Aldolase A, fructose-bisphosphate (SEQ ID NOs:2, 68); Aldolase C, fructose-bisphosphate (SEQ ID NOs:3, 69); Triosephosphate isomerase 1 (SEQ ID NOs:4, 65, 70); similar to Glyceraldhyde-3-phosphate dehydrogenaseisoform 1 (SEQ ID NOs:5, 71, 72); Enolase 1, alpha non-neuron (SEQ ID NOs:6, 73); Enolase 2, gamma neuronal (SEQ ID NOs:7, 74); Lactate dehydrogenase B (SEQ ID NOs:8, 75); Glycerol, phosphate dehydrogenase 2, mitochondrial (SEQ ID NOs:9, 76, 77); Glutamate-ammonia ligase (Glutamine synthetase) (SEQ ID NOs:10, 78, 79); Dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase complex) (SEQ ID NOs:11, 80, 66); Isocitrate dehydrogenase 3 (NAD+) alpha, isoform CRA_(SEQ ID NOs:12, 81); Malate dehydrogenase, cytoplasmic (SEQ ID NOs:13, 82); NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8 (SEQ ID NOs:14, 83); NADH dehydrogenase (ubiquinone) Fe-S protein 1 (SEQ ID NOs:15, 84, 67); NADH dehydrogenase (ubiquinone) Fe-S protein 8 (SEQ ID NOs:16, 85); Ubiquinol-cytochrome-c reductase complex core protein 1 (SEQ ID NOs:17, 86); ATP synthase, H+ transporting, mitochondrial F0 complex, subunit d (SEQ ID NOs:18, 87, 88); Creatine kinase, brain (SEQ ID NOs:19, 89); Heat shock protein 8 (SEQ ID NOs:20, 90, 91); Heat shock protein 9 (SEQ ID NOs:21, 92); Hsp70 homolog perinuclear form (mortalin mot-2) (SEQ ID NO:22); Protein disulfide isomerase associated 3 (SEQ ID NOs:23, 93); ATPase, H+ transporting, lysosomal V1 subunit A (SEQ ID NOs:24, 94); Proteasome 26S subunit, ATPase, 4 (SEQ ID NOs:25, 95, 96); Proteasome subunit alpha type-2 (SEQ ID NOs:26, 97); Ubiquitin carboxy-terminal hydrolase L1, isoform CRA_b (SEQ ID NOs:27, 98); Valosin containing protein, isoform CRA_b (SEQ ID NOs:28, 99); 3-Hydroxyisobutyrate dehydrogenase (SEQ ID NOs:29, 100); Biphenyl hydrolase-like (SEQ ID NOs:30, 101); Haloacid dehalogenase-like hydrolase domain containing 2 (SEQ ID NOs:31, 102); Beta-actin (aa 27-375) (SEQ ID NOs:32, 103); Gamma-actin (SEQ ID NOs:33, 104); Profilin 2, isoform CRA_b (SEQ ID NOs:34, 105, 106); Transgelin 3 (SEQ ID NOs:35, 107); Annexin A6, isoform CRA_b (SEQ ID NOs:36, 108, 109); Internexin neuronal intermediate filament protein, alpha (SEQ ID NOs:37, 110); Neurofilament, light polypeptide (SEQ ID NOs:38, 111); Glial fibrillary acidic protein (SEQ ID NOs:39, 112, 113); Tubulin, alpha 1B (SEQ ID NOs:40, 114); Tubulin, beta (SEQ ID NOs:41, 115); Tubulin, beta 3 (SEQ ID NOs:42, 116); Dihydropyrimidinase-like 2 (SEQ ID NOs:43, 117); Dihydropyrimidinase-like 4, isoform CRA_c (SEQ ID NOs:44, 118); Brain abundant, membrane attached signal protein 1 (SEQ ID NOs:45, 119); RAB1B, member RAS oncogene family; isoform CRA_a (SEQ ID NOs:46, 120); RAB3A, member RAS oncogene family (SEQ ID NOs:47, 121); RAB6A, member RAS oncogene family (SEQ ID NOs:48, 122); Guanosine diphosphate dissociation inhibitor 1 (SEQ ID NOs:49, 123); Phospholipase C-alpha (SEQ ID NOs:51, 125); Calcineurin B, type I (SEQ ID NOs:52, 126, 127); Calbindin-28K (SEQ ID NOs:53, 128); Calretinin (SEQ ID NOs:54, 129); Visinin-like 1 (SEQ ID NOs:55, 130); Chloride intracellular channel 4 (mitochondrial) (SEQ ID NOs:56, 131); mCG7191 (Raf Kinase Inhibitor Protein (RKIP)) ((SEQ ID NOs:57, 132); Peroxiredoxin 1 (SEQ ID NOs:60, 135); Peroxiredoxin 3 (SEQ ID NOs:61, 136); Pyridoxal (pyridoxine, vitamin B6) kinase (SEQ ID NOs:62, 137); and Guanine nucleotide binding protein, alpha o isoform B (SEQ ID NOs:63, 138, 139).
[0075] In a further embodiment, the invention provides as item 10 the soluble neuregulin-1 isoform of item 9, wherein said protein is dihydropyrimidinase-like 2 (SEQ ID NOs:43, 117) and/or valosin-containing protein, isoform CRA_b (SEQ ID NOs:28, 99).
[0076] A further aspect of the invention is item 11 which is a protein of Table 2 for the prevention, amelioration and/or treatment of a neurological disorder.
[0077] Also provided is item 12 which relates to a soluble neuregulin-1 isoform of any one of items 2-10, wherein the loss of neurons is associated with a neurological disorder.
[0078] Also provided is item 13 which is the soluble neuregulin-1 isoform of any one of items 1-10 or 12 or the protein of item 11, wherein the neurological disorder is selected from the group consisting of schizophrenia, in particular cognition-related aspects of schizophrenia; Parkinson's disease; Alzheimer's disease; Multiple Sclerosis (MS); Amyotrophic Lateral Sclerosis (ALS); epilepsy; stroke; traumatic brain injury; spinal chord injury; bipolar disorders; depression; frontotemporal dementia; seizures; ischemia; neuropathy, particularly diabetic neuropathy; neuralgia; neuropathic pain; and inclusion-body myopathy.
[0079] Item 14 is directed at a preferred embodiment of item 13, wherein the neurological disorder is Parkinson's disease.
[0080] Also provided is as item 15 the soluble neuregulin-1 isoform of any one of items 1-10 or 12-14, which is characterized in that it passes the blood brain barrier.
[0081] In one embodiment of the soluble neuregulin-1 isoform of any one of items 1-10 or 12-15 the neuregulin-1 isoform is a neuregulin-1β1 isoform. This embodiment is also referred to as item 16.
[0082] In a further embodiment, item 17 relates to the soluble neuregulin-1 isoform of any one of items 1-10 or 12-16, which is characterized in that it comprises the extracellular domain of neuregulin-1 or fragments thereof, particularly the EGF-like domain or the EGF-like domain, the IgG-like domain and the heparan sulfate binding motif.
[0083] In a further embodiment, item 18 provides the soluble neuregulin-1 isoform of any one of items 1-10 or 12-17, wherein the isoform comprises SEQ ID NO:1.
[0084] In a further embodiment, item 19 provides the soluble neuregulin-1 isoform of any one of the items 15-17, wherein the isoform comprises:
[0085] (a) nucleotides 46-634 of SEQ ID NO:64,
[0086] (b) amino acids 176-246 of SEQ ID NO:1, and/or
[0087] (c) amino acids 2-246 of SEQ ID NO:1.
[0088] In a further embodiment, the invention provides as item 20 the soluble neuregulin-1 isoform of item 19 which comprises amino acids 2-246 of SEQ ID NO:1.
[0089] In a further embodiment, the invention provides as item 21 the soluble neuregulin-1 isoform of any one of items 1-10 or 12-20 or the protein of item 11 in combination with a further active agent.
[0090] In a further embodiment, the invention provides as item 22 the soluble neuregulin-1 isoform of item 21 or the protein of item 21, wherein the further active agent is an agent for the treatment of neurological conditions and/or neurological disorders.
[0091] In a further embodiment, item 23 provides the soluble neuregulin-1 isoform of item 22 or the protein of item 22, wherein the further agent is selected from compounds affecting catecholamine metabolism, acetylcholine esterase inhibitors, MAO-B- or COMT-inhibitors, Memantine-type channel blockers, dopamine or serotonine receptor agonists or antogonists, catecholamine or serotonine reuptake inhibitors or any type of antipsychotic medication like clozapine or olanzapine or gabapentin-like drugs in the treatments of Alzheimer's and Parkinson's disease, schizophrenia, bipolar disorder, depression or other neurological conditions.
[0092] In a further embodiment, the invention provides as item 24 the soluble neuregulin-1 isoform of items 21 or 22 or protein of items 21 or 22, wherein the further agent is an agent for the treatment of psychotic disorders such as schizophrenia, bipolar disorders and depression, e.g. olanzapine or clozapine.
[0093] In a further embodiment, the invention provides as item 25 the soluble neuregulin-1 isoform of items 21 or 22 or the protein of items 21 or 22, wherein the further agent is an agent for the treatment of Parkinson's disease.
[0094] In a further embodiment, the invention provides as item 26 the soluble neuregulin-1 isoform of items 21 or 22 or the protein of items 21 or 22, wherein the further agent is an agent for the treatment of Alzheimer's disease.
[0095] In a further embodiment, the invention provides as item 27 the soluble neuregulin-1 isoform of items 21 or 22 or the protein of items 21 or 22, wherein the further agent is an agent for the treatment of Multiple Sclerosis (MS).
[0096] In a further embodiment, the invention provides as item 28 the soluble neuregulin-1 isoform of items 21 or 22 or the protein of items 21 or 22, wherein the further agent is an agent for the treatment of Amyotrophic Lateral Sclerosis (ALS).
[0097] In a further embodiment, the invention provides as item 29 the soluble neuregulin-1 isoform of items 21 or 22 or the protein of items 21 or 22, wherein the further agent is an agent for the treatment of epilepsy.
[0098] In a further embodiment, the invention provides as item 30 the soluble neuregulin-1 isoform of items 21 or 22 or the protein of items 21 or 22, wherein the further agent is an agent for the treatment of stroke.
[0099] In a further embodiment, the invention provides as item 31 the soluble neuregulin-1 isoform of items 21 or 22 or the protein of items 21 or 22, wherein the further agent is an agent for the treatment of traumatic brain injury.
[0100] In a further embodiment, item 32 provides the soluble neuregulin-1 isoform of items 21 or 22 or the protein of items 21 or 22, wherein the further agent is an agent for the treatment of spinal chord injury.
[0101] In a further aspect item 33 relates to a nucleic acid molecule encoding the soluble neuregulin-1 isoform of any one of items 15-20, preferably the nucleic acid molecule comprising SEQ ID NO:64.
[0102] In another aspect, item 34 provides the nucleic acid molecule of item 33 for the uses of any one of items 1-10, 12-14 or 22-32.
[0103] Also provided is item 35 which is a nucleic acid molecule encoding a protein of Table 2 for the use of any one of items 11, 13, 14, or 22-32.
[0104] A further aspect, item 36 relates to a pharmaceutical composition comprising as active agent a soluble neuregulin-1 isoform of any one of items 15-20 and/or a nucleic acid molecule encoding a soluble neuregulin-1 isoform of item 33 and optionally a pharmaceutically active carrier.
[0105] In another aspect the invention provided item 37 which is a method for studying a neurological disorder, the molecular mechanism of, the physiological processes associated with a loss of neurons, or a disorder associated with a loss of neurons comprising:
[0106] (a) administering a neuregulin-1 isoform to a cell or a non-human vertebrate animal;
[0107] (b) subjecting said cell or an organ or tissue sample of said animal to a proteome analysis or gene expression analysis; and
[0108] (c) comparing the proteome analysis or the gene expression analysis to the respective analysis of a control cell or a control non-human animal.
[0109] In one embodiment, the invention provides as item 38 the method of item 37, wherein the neurological disorder is selected from the group consisting of schizophrenia, in particular cognition-related aspects of schizophrenia; Parkinson's disease; Alzheimer's disease; Multiple Sclerosis (MS); Amyotrophic Lateral Sclerosis (ALS); epilepsy; stroke; traumatic brain injury; spinal chord injury; bipolar disorders; depression; frontotemporal dementia; seizures; ischemia; neuropathy, particularly diabetic neuropathy; neuralgia; neuropathic pain; and inclusion-body myopathy.
[0110] Item 39 relates to the method of items 37 or 38, wherein the neurological disorder is Parkinson's disease.
[0111] A preferred embodiment is item 40 which is the method of any one of items 37-39, wherein the non-human vertebrate animal is selected from the group consisting of mouse, rat, rabbit, hamster, bird, cat, sheep, bovine, and horse.
[0112] In a further embodiment, the invention provides as item 41 the method of item 40, wherein the non-human vertebrate animal is a mouse, preferably a mouse model for a neurological disorder.
[0113] In a further embodiment, item 42 provides the method of item 41, wherein said mouse model is for Parkinson's disease, preferably by inducing neuronal death with 6-hydroxydopamine (6-OHDA) or the A53T alpha synuclein transgenic mouse or for Alzheimer's disease, preferably the APP/PS mouse model.
[0114] Also within the ambit of the invention is item 43 which is, as also described herein above, a method for identifying and/or testing an agent that alters the expression and/or function of any one of the proteins of Table 2 or the nucleic acids encoding a protein of Table 2 comprising:
[0115] (a) administering said agent to a cell or a non-human vertebrate animal;
[0116] (b) measuring or monitoring the expression and/or function of said proteins or nucleic acid molecules encoding said proteins; and
[0117] (c) comparing the expression and/or function of said proteins or nucleic acid molecules to the expression and/or function of said proteins or nucleic acid molecules in a control cell or a control non-human vertebrate animal.
[0118] Also the following aspects and preferred embodiments are within the ambit of the invention:
[0119] Before outlining these further aspects and embodiments, some additional definitions of terms frequently used in this specification are provided. These terms will, in each instance of its use, have the respectively defined meaning and preferred meanings.
[0120] As used herein, the term "isolated" refers to a molecule which is substantially free of other molecules with which it is naturally associated with. An isolated molecule is thus free of other molecules that it would encounter or contact in a living animal in nature, i.e. outside an experimental setting. Preferably, the antibody or fragment thereof of the present invention is an isolated antibody or fragment thereof.
[0121] As used herein, the term "polypeptide" refers to both naturally occurring polypeptides and synthesized polypeptides that may include naturally or non-naturally occurring amino acids. Polypeptide can also be modified, e.g. can comprise a chemical modification of a side chain or a free amino or carboxy-terminus of a natural or non-naturally occurring amino acid. This chemical modification includes detectable labels, such as a fluorophore. A polypeptide may also comprise further modifications such as the side chain or a free amino or carboxy-terminus of an amino acid of the polypeptide may be modified by e.g. glycosylation, amidation, phosphorylation, ubiquitination, e.t.c. Such modification can be effect in vitro or in a host-cell i.e. in vivo, as is well known in the art of protein science. For example, a suitable chemical modification motif, e.g. glycosylation sequence motif present in the amino acid sequence of the polypeptide will cause it to be glycosylated in vivo. A polypeptide according to the invention has in a preferred embodiment not more than 300 amino acids, preferably not more than 244 amino acids and most preferably not more than 200 amino acids.
[0122] As used throughout this application, the phrase "single amino acid substitution, deletion and/or insertion" of a polypeptide generally refers to a modified version of the polypeptide, e.g. one amino acid of the polypeptide may be deleted, inserted and/or substituted. If the polypeptide comprises several single amino acid substitutions, deletions and/or insertions then the total number of such substitutions, deletions and/or insertions is indicated in each case. Said insertion is an insertion of the indicated number of single amino acids into the original polypeptide or protein. If the polypeptide comprises one or more single amino acid substitutions, said substitutions may in each case independently be a conservative or a non-conservative substitution, preferably a conservative substitution. In some embodiments, a substitution also includes the exchange of a naturally occurring amino acid with a not naturally occurring amino acid. In a most preferred embodiment, all substitutions are of conservative nature as further defined below. A conservative substitution comprises the substitution of one amino acid with another amino acid having a chemical property similar to the amino acid that is substituted. Preferably, the conservative substitution is a substitution selected from the group consisting of:
[0123] (i) a substitution of a basic amino acid with another, different basic amino acid;
[0124] (ii) a substitution of an acidic amino acid with another, different acidic amino acid;
[0125] (iii) a substitution of an aromatic amino acid with another, different aromatic amino acid;
[0126] (iv) a substitution of a non-polar, aliphatic amino acid with another, different non-polar, aliphatic amino acid; and
[0127] (v) a substitution of a polar, uncharged amino acid with another, different polar, uncharged amino acid.
[0128] A basic amino acid is preferably selected from the group consisting of arginine, histidine, and lysine. An acidic amino acid is preferably aspartate or glutamate. An aromatic amino acid is preferably selected from the group consisting of phenylalanine, tyrosine and tryptophane. A non-polar, aliphatic amino acid is preferably selected from the group consisting of glycine, alanine, valine, leucine, methionine and isoleucine. A polar, uncharged amino acid is preferably selected from the group consisting of serine, threonine, cysteine, proline, asparagine and glutamine. In contrast to a conservative amino acid substitution, a non-conservative amino acid substitution is the exchange of one amino acid with any amino acid that does not fall under the above-outlined conservative substitutions (i) through (v).
[0129] If a polypeptide comprises one or an indicated number of single amino acid deletions, then said number of amino acids present in the reference polypeptide have been removed.
[0130] Reference will be made in the following to preferred amino acid sequences which are outlined in the table below:
TABLE-US-00001 SEQ ID NO: Amino Acid Sequence Annotation 140 CPNEFTGDRCQNYVMASFYKHLGIEFME Fragment of EGF-like domain of B1 neuregulin 1 141 CPNEFTGDRCQNYVMASFYK Fragment of EGF-like domain of B2 neuregulin 1 142 CPNEFTGDRCQNYVMASFYSTSTPFLSLPE Fragment of EGF-like domain of B3 (long) neuregulin 1 143 CPNEFTGDRCQNYVMASFYS Fragment of EGF-like domain of B3 (short) neuregulin 1 144 CQPGFTGARCTENVPMKVQNQEK Fragment of EGF-like domain of a neuregulin 1 145 CQPGFTGARCTENVPMKVQNQES Fragment of EGF-like domain of a3 neuregulin 1 146 CQPGFTGARCTENVPMKVQNQEKHLGIEFIE Fragment of EGF-like domain of a1A neuregulin 1 147 SHLVKCAEKEKTFCVNGGECFMVKDLSNPS EGF-like domain of B1 RYLCKCPNEFTGDRCQNYVMASFYKHLGIE neuregulin 1 FME 148 SHLVKCAEKEKTFCVNGGECFMVKDLSNPS EGF-like domain of B2 RYLCKCPNEFTGDRCQNYVMASFYK neuregulin 1 149 SHLVKCAEKEKTFCVNGGECFMVKDLSNPS EGF-like domain of B3 (long) RYLCKCPNEFTGDRCQNYVMASFYSTSTPFL neuregulin 1 SLPE 150 SHLVKCAEKEKTFCVNGGECFMVKDLSNPS EGF-like domain of B3 (short) RYLCKCPNEFTGDRCQNYVMASFYS neuregulin 1 151 SHLVKCAEKEKTFCVNGGECFMVKDLSNPS EGF-like domain of a RYLCKCQPGFTGARCTENVPMKVQNQEK neuregulin 1 152 SHLVKCAEKEKTFCVNGGECFMVKDLSNPS EGF-like domain of a3 RYLCKCQPGFTGARCTENVPMKVQNQES neuregulin 1 153 SHLVKCAEKEKTFCVNGGECFMVKDLSNPS EGF-like domain of a1A RYLCKCQPGFTGARCTENVPMKVQNQEKH neuregulin 1 LGIEFIE 154 MSERKEGRGKGKGKKKERGSGKKPESAAG heparin binding domain of SQSPALPPRLKEMKSQESAAGSK neuregulin 1 (alternative 1) 155 SERKEGRGKGKGKKKERGSGKKPESAAGSQ heparin binding domain of SPALPPQLKEMKSQESAAGSKLVLRCETSSE neuregulin 1 (alternative 2) YSLRFKWFKNGNELNRKNKPQNIKIQKKPG KSELRINKASLADSGEYMCKVISKLG 156 PQLKEMKSQESAAGSKLVLRCETSSEYSLRF heparin binding domain of KWFKNGNELNRKNKPQNIKIQKKPGKSELRI neuregulin 1 (alternative 3) NKASLADSGEYMCKVISKLGNDSASANIT 157 SERKEGRGKGKGKKKERGSGKKPESAAGSQ heparin binding domain of SPALPPQLKEMKSQESAAGSKLVLRCETSSE neuregulin 1 (alternative 4) YSLRFKWFKNGNELNRKNKPQNIKIQKKPG KSELRINKASLADSGEYMCKVISKLGNDSAS ANIT 158 VISKLGNDSASANITTVESNEHTGMPASTEGA glycosylated domain of YVSSESPIRISVSTEGANTSSSTSTSTTGT neuregulin 1 159 <as outlined in the sequence protocol> erbB3 receptor 160 <as outlined in the sequence protocol> erbB4 receptor
[0131] The inventors of the present invention have found that the entire extracellular domain (ECD) of neuregulin can cross the blood brain barrier (see examples below). A smaller fragment of neuregulin Nrg1β1 containing only the EGF-like domain (Thr176-Lys246 of SEQ ID NO:1, 8 kDa) was also capable of passing the intact adult blood brain barrier, yet showed a rather unselective interaction with ErbB-receptors.
[0132] It was one object of the present invention to provide a recombinant neuregulin polypeptide which effectively passes the blood brain barrier and/or which selectively interacts with the target receptors such as erbB3 receptor and/or erbB4 receptor without exhibiting undesired mitogenic properties.
[0133] Based on in silico modelling, the inventors assessed that the interaction with the target receptors could be improved by selecting shorter neuregulin fragments and also by generating recombinant polypeptides by fusing the EGF-like domain of neuregulin or fragments thereof to optimized heparin-binding domain(s) and/or to polybasic polypeptides capable of interacting with heparin and/or heparan sulphate. Without being bound by theory, an attractive hypothesis is that neuregulin may be concentrated more specifically at synapses through binding to heparin-like glycosaminoglycans in the extracellular matrix. This may reduce off-target effect, e.g. the activation of receptors other than erbB3 and erbB4 by of the EGF-like domain which may induce cell division which is unwanted due to the risk of cancerogenesis.
[0134] Thus, the fusion polypeptides of the invention as outlined below provide therapeutic compounds that comprise only a minimal essential system to bind and activate the respective target receptors. At the same time the size of the polypeptides can be reduced, e.g. by using short linker molecules between the domains or by directly linking the domains to each other. Care was taken to optimize the heparin binding domains to make them as short as possible while retaining their heparin-binding function (see e.g. figures 5 and 6 below).
[0135] Accordingly, in a further aspect the invention relates to a polypeptide, wherein the polypeptide comprises or consists of an EGF-like domain (EGFLD1) selected from the group consisting of SEQ ID NO: 140-146 (i.e. SEQ ID NO: 140, 141, 142, 143, 144, 145 and 146), wherein said EGF-like domain may comprise up to one, two, three, four or up to five single amino acid deletions, insertions and/or mutations and wherein said EGF-like domain optionally comprises up to 5, 10, 15 20, 25, 30, 35 or up to 40 and most preferably up to 30 additional amino acids at its C- and/or N-terminus.
[0136] In one embodiment the invention relates to a polypeptide, wherein the polypeptide comprises or consists of an EGF-like domain (EGFLD1) according to SEQ ID NO: 147, wherein said EGF-like domain may comprise up to one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or up to thirteen single amino acid deletions, insertions and/or mutations and wherein said EGF-like domain optionally comprises up to 5, 10, 15, 20, 25, 30, 35 or up to 40 and most preferably up to 30 additional amino acids at its C- and/or N-terminus.
[0137] In the context of EGF-like domains that are comprised in the polypeptides of the invention, it is preferred that said single amino acid deletion(s) and/or mutation(s) that may be present are not at any of the following positions of said first and, if present, further EGF-like domains, i.e. of SEQ ID NO: 140-146 (i.e. SEQ ID NO: 140, 141, 142, 143, 144, 145 and 146); position 1 (cystein), position 5 (phenylanlanine), position 6 (threonine), position 7 (glycine), position 9 (arginine), position 10 (cystein) and/or position 14 (valine). In other words, it is preferred that the amino acids at position 1, 5, 6, 7, 9, 10 and/or 14 are as specified in SEQ ID NO: 140-146 (i.e. SEQ ID NO: 140, 141, 142, 143, 144, 145 and 146) and are not mutated, deleted or shifted by insertion. Each position is counted from the N-terminus of the sequence according to any of SEQ ID NO: 140-146 (i.e. SEQ ID NO: 140, 141, 142, 143, 144, 145 and 146), as is usual practice in the field. For example, the first position (position 1) refers to the first amino acid in SEQ ID NO 140-146 (i.e. SEQ ID NO: 140, 141, 142, 143, 144, 145 and 146) which is a cystein.
[0138] Preferably, the EGF-like domain (EGFLD1) is selected from the group consisting of SEQ ID NO: 147-153 (i.e. SEQ ID NO: 147, 148, 149, 150, 151, 152 and 153) and wherein said EGF-like domain may in total comprise up to one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or up to thirteen single amino acid deletions, insertions and/or mutations. In a further preferred embodiment of the aforementioned aspect and preferred embodiment, the EGF-like domain (EGFLD1) is selected from the group consisting of SEQ ID NO: 140-143 (i.e. SEQ ID NO: 140, 141, 142 or 143) or SEQ ID NO: 147-150 (i.e. SEQ ID NO: 147, 148, 149 or 150), i.e. comprises a neuregulin1-beta EGF-like domain.
[0139] Providing a polypeptide that comprises two or more EGF-like domains has been predicted by the inventors to improve the receptor binding ability of the polypeptide of the invention.
[0140] Thus, in a further preferred embodiment the polypeptide of the invention further comprises at least one additional EGF-like domain, wherein each additional EGF-like domain is independently selected from the group consisting of SEQ ID NO: 140-153 (i.e. SEQ ID NO: 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152 and 153), wherein each additional EGF-like domain may comprise up to one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or up to thirteen single amino acid deletions, insertions and/or mutations. In a more preferred embodiment, all EGF-like domains comprised in the polypeptide of the invention in total do not comprise more than five, four, three, two or more than one single amino acid deletions, insertions or mutation.
[0141] Thus, the polypeptide of the invention comprises in one embodiment at least a second EGF-like domain (EGFLD2) selected (independently from any other EGF-like domain that may be present) from the group consisting of SEQ ID NO: 140-153 (i.e. SEQ ID NO: 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152 and 153), wherein the second EGF-like domain may comprise up to one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or up to thirteen single amino acid deletions, insertions and/or mutations.
[0142] In a more preferred embodiment, the polypeptide of the invention comprises a first EGF-like domain (EGFLD1) according to SEQ ID NO: 147 and a second EGF-like domain (EGFLD2) according to SEQ ID NO: 147, wherein the first and second EGF-like domain may together comprise up to one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or up to thirteen single amino acid deletions, insertions and/or mutations.
[0143] Also preferred is the polypeptide of the invention, wherein the polypeptide further comprises a heparin binding domain (HBD). By in silico computational analysis minimal essential heparin binding domains have been identified that based on their charge profile and preferably the presence of an Ig-like domain are expected to improve the specificity of binding of the polypeptides of the invention, thereby reducing any mitogenic effect that the polypeptide may have. Thus, in a preferred embodiment the heparin binding domain of the polypeptide according to the invention has an amino acid sequence according to any of SEQ ID NO: 154, 155, 156 or 157 (most preferably 157) and wherein the heparin binding domain may comprise up to one, two, three, four, five, six, seven, eight, nine, ten, eleven or up to twelve (most preferably up to five) single amino acid deletions, insertions and/or mutations. If the heparin binding domain has one or more single amino acid deletions, insertions and/or mutations it is preferred that between 5% and 40%, more preferably between 15% and 35% and most preferably between 20% and 30% of all amino acids of the heparin binding domain are one or more of the following amino acids: histidine, arginine and lysine.
[0144] A "heparin binding domain" as used herein is capable of binding to heparin and/or to heparan sulphate. Heparin is synthesized in cells as a proteoglycan (PG) having in one embodiment a molecular weight of at least 106 Daltons. Heparin is a repeating linear copolymer of 1→4 linked oronic acid and glucosamine residues. Heparan sulfate is a member of the glycosaminoglycan family of carbohydrates and is very closely related in structure to heparin. The most common disaccharide unit within heparan sulfate is composed of a glucuronic acid (GlcA) linked to N-acetylglucosamine (GlcNAc) typically making up around 50% of the total disaccharide units.
[0145] Various heparin and heparan sulphate binding proteins are known to the average skilled person and their binding domains are well characterized (see e.g. Hileman, "Glycosaminoglycan-protein interactions: definition of consensus sites in glycosaminoglycan binding proteins", BioEssays 20:156-167, 1998 John Wiley & Sons, Inc.). In one embodiment, the heparin binding domain comprised in a preferred polypeptide of the invention is an Ig-like (Ig-L) domain that binds to constituents of the extracellular matrix such as heparin (see e.g. Loch, J. A. & Fischbach, G. D. (1995) J. Cell Biol. 130, 127-135.). One preferred heparin binding domain of the invention is an Immunoglobulin-like (Ig-like) domain and most preferably a C2-type immunoglobulin-like domain.
[0146] In a more preferred embodiment of the polypeptide of the invention, the polypeptide comprises a heparin binding domain (HBD) having an amino acid sequence according to any of SEQ ID NO: 154, 155, 156 or 157 (most preferably 157) linked to an EGF-like domain (EGFLD1) selected from the group consisting of SEQ ID NO: 140-146 (i.e. SEQ ID NO: 140, 141, 142, 143, 144, 145 and 146) via a linker, wherein the EGF-like domain and said heparin binding domain together may in total comprise up to one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or thirteen single amino acid deletions, insertions and/or mutations. The linker is preferably selected from a covalent bond, a chemical linker as described herein and a polypeptide of between 1 and 45 amino acids more preferably of between 1 and 25 amino acids and most preferably of between 1 and 10 amino acids.
[0147] In this embodiment it is preferred that between 20% and 50%, more preferably between 20% and 35% and most preferably between 23% and 35% of all amino acids of the heparin binding domain and/or linker are one or more of the following amino acids; histidine, arginine and lysine.
[0148] In another embodiment it is preferred that at least 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28% or at least 29% of all amino acids of the heparin binding domain and/or linker are amino acids selected from the group consisting of histidine, arginine and lysine.
[0149] Further preferred embodiments of the polypeptide of the invention comprises or consists of a linker, a HBD and an EGFLD1, wherein the linker is a peptide, linking the HBD as defined herein to the EGFLD1 as defined herein, wherein the polypeptide further has the features as listed in the table below:
TABLE-US-00002 Total number of single amino acid deletions, Linker size Content of His, Arg insertions and/or (length in and Lys in HBD over mutations in HBD and number of the entire length of EGFLD1 together: amino acids) the HBD between 0 and 10 between 0 and 45 between 20% and 35% between 0 and 10 between 0 and 45 between 23% and 30% between 0 and 10 between 0 and 10 between 20% and 35% between 0 and 10 between 0 and 10 between 23% and 30% between 0 and 3 between 0 and 45 between 20% and 35% between 0 and 3 between 0 and 45 between 23% and 30% between 0 and 3 between 0 and 10 between 20% and 35% between 0 and 3 between 0 and 10 between 23% and 30%
[0150] Further preferred embodiments of the polypeptide of the invention comprises or consists of a linker, a HBD and an EGFLD1, wherein said linker is a chemical linker or a polypeptide of between 0 and 25 amino acids, linking the HBD as shown to the EGFLD1 as defined herein, wherein the polypeptide further has the features as listed in the table below:
TABLE-US-00003 Total number of single amino acid deletions, Content of His, Arg insertions and/or and Lys in HBD over SEQ ID NO mutations in HBD and the entire length of of the HBD EGFLD1 together: the HBD 154 between 0 and 10 between 20% and 35% 154 between 0 and 10 between 23% and 30% 154 between 0 and 3 between 20% and 35% 154 between 0 and 3 between 23% and 30% 155 between 0 and 10 between 20% and 35% 155 between 0 and 10 between 23% and 30% 155 between 0 and 3 between 20% and 35% 155 between 0 and 3 between 23% and 30% 156 between 0 and 10 between 20% and 35% 156 between 0 and 10 between 23% and 30% 156 between 0 and 3 between 20% and 35% 156 between 0 and 3 between 23% and 30% 157 between 0 and 10 between 20% and 35% 157 between 0 and 10 between 23% and 30% 157 between 0 and 3 between 20% and 35% 157 between 0 and 3 between 23% and 30%
[0151] Further preferred embodiments of the polypeptide of the invention comprises or consists of a linker, a HBD and an EGFLD1, wherein the linker is a chemical linker or a polypeptide of between 0 and 25 amino acids, linking the HBD as shown to the EGFLD1 according to SEQ ID NO: 147, wherein the polypeptide further has the features as listed in the table below:
TABLE-US-00004 Total number of single amino acid deletions, Content of His, Arg insertions and/or and Lys in HBD over SEQ ID NO mutations in HBD and the entire length of of the HBD EGFLD1 together: the HBD 154 between 0 and 10 between 20% and 35% 154 between 0 and 10 between 23% and 30% 154 between 0 and 3 between 20% and 35% 154 between 0 and 3 between 23% and 30% 155 between 0 and 10 between 20% and 35% 155 between 0 and 10 between 23% and 30% 155 between 0 and 3 between 20% and 35% 155 between 0 and 3 between 23% and 30% 156 between 0 and 10 between 20% and 35% 156 between 0 and 10 between 23% and 30% 156 between 0 and 3 between 20% and 35% 156 between 0 and 3 between 23% and 30% 157 between 0 and 10 between 20% and 35% 157 between 0 and 10 between 23% and 30% 157 between 0 and 3 between 20% and 35% 157 between 0 and 3 between 23% and 30%
[0152] Further preferred embodiments of the polypeptide of the invention comprises or consists of a linker, a HBD and an EGFLD1, wherein the linker is a chemical linker or a polypeptide of between 0 and 5 amino acids, linking the HBD as shown to the EGFLD1 according to SEQ ID NO: 147, wherein the polypeptide further has the features as listed in the table below:
TABLE-US-00005 Total number of single amino acid deletions, Content of His, Arg insertions and/or and Lys in HBD over SEQ ID NO mutations in HBD and the entire length of of the HBD EGFLD1 together: the HBD 154 between 0 and 10 between 20% and 35% 154 between 0 and 10 between 23% and 30% 154 between 0 and 3 between 20% and 35% 154 between 0 and 3 between 23% and 30% 155 between 0 and 10 between 20% and 35% 155 between 0 and 10 between 23% and 30% 155 between 0 and 3 between 20% and 35% 155 between 0 and 3 between 23% and 30% 156 between 0 and 10 between 20% and 35% 156 between 0 and 10 between 23% and 30% 156 between 0 and 3 between 20% and 35% 156 between 0 and 3 between 23% and 30% 157 between 0 and 10 between 20% and 35% 157 between 0 and 10 between 23% and 30% 157 between 0 and 3 between 20% and 35% 157 between 0 and 3 between 23% and 30%
[0153] Further preferred embodiments of the polypeptide of the invention comprises or consists of a linker, a HBD and an EGFLD1, wherein the linker is a chemical linker or a polypeptide of between 0 and 5 amino acids, linking the HBD as shown to the EGFLD1 according to SEQ ID NO: 140, wherein the polypeptide further has the features as listed in the table below:
TABLE-US-00006 Total number of single amino acid deletions, Content of His, Arg insertions and/or and Lys in HBD over SEQ ID NO mutations in HBD and the entire length of of the HBD EGFLD1 together: the HBD 154 between 0 and 10 between 20% and 35% 154 between 0 and 10 between 23% and 30% 154 between 0 and 3 between 20% and 35% 154 between 0 and 3 between 23% and 30% 155 between 0 and 10 between 20% and 35% 155 between 0 and 10 between 23% and 30% 155 between 0 and 3 between 20% and 35% 155 between 0 and 3 between 23% and 30% 156 between 0 and 10 between 20% and 35% 156 between 0 and 10 between 23% and 30% 156 between 0 and 3 between 20% and 35% 156 between 0 and 3 between 23% and 30% 157 between 0 and 10 between 20% and 35% 157 between 0 and 10 between 23% and 30% 157 between 0 and 3 between 20% and 35% 157 between 0 and 3 between 23% and 30%
[0154] Also preferred is a polypeptide of the invention, which has at least two EGF-like domains and a heparin binding domain, preferably a heparin domain as outlined in the above tables. A polypeptide according to this embodiment may optionally comprise one or two linker, linking said domains to each other in any order. Most preferably the aforementioned embodiment has the following features, wherein each linker has a length independently selected from the range as outlined below:
TABLE-US-00007 Maximum number of single amino acid deletions, insertions Linker Content of His, Arg and/or mutations in size (length and Lys in HBD over HBD, EGFLD1 and in number of the entire length of EGFLD2 together: amino acids) the HBD between 0 and 10 between 0 and 45 between 20% and 35% between 0 and 10 between 0 and 45 between 23% and 30% between 0 and 10 between 0 and 10 between 20% and 35% between 0 and 10 between 0 and 10 between 23% and 30% between 0 and 3 between 0 and 45 between 20% and 35% between 0 and 3 between 0 and 45 between 23% and 30% between 0 and 3 between 0 and 10 between 20% and 35% between 0 and 3 between 0 and 10 between 23% and 30%
[0155] In a further preferred embodiment of the polypeptide of the invention, the polypeptide comprises a heparin binding domain (HBD) having an amino acid sequence according to any of SEQ ID NO: 154, 155, 156 or 157 (most preferably 157) linked to an EGF-like domain (EGFLD1) according to SEQ ID NO: 147 via a linker, wherein the EGF-like domain and said heparin binding domain together may in total comprise up to one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or thirteen single amino acid deletions, insertions and/or mutations. The linker is preferably selected from a covalent bond, a chemical linker as described herein and a polypeptide of between 1 and 45 amino acids more preferably of between 1 and 25 amino acids and most preferably of between 1 and 10 amino acids.
[0156] In this embodiment it is preferred that at least 20%, 22%, 24%, 26%, 28%, or at least 29% of all amino acids of the heparin binding domain and/or linker are amino acids selected from the group consisting of histidine, arginine and lysine.
[0157] In a further preferred embodiment of the polypeptide of the invention said heparin binding domain is at the N-terminus or the C-terminus of the EGF-like domain and most preferably at the N-terminus.
[0158] A further preferred embodiment is a polypeptide according to the invention, wherein the polypeptide further comprises a linker between the EGF-like domain EGFLD1 and the second EGF-like domain EGFLD2, between any two or more neighbouring EGF-like domains, between said heparin binding domain and said EGF-like domain EGFLD1 and/or between said heparin binding domain and said second EGF-like domain EGFLD2.
[0159] Preferably, the polypeptide according to the invention has a structure selected from:
[0160] EGFLD1-linker-EGFLD2,
[0161] HBD-linker-EGFLD1-linker-EGFLD2,
[0162] EGFLD1-linker-HBD-linker-EGFLD2, or
[0163] EGFLD1-linker-EGFLD2-linker-HBD.
[0164] As used herein the term "linker" refers to a linker selected from a covalent bond, a chemical linker and a polypeptide, wherein the polypeptide preferably has a length of between 1 and 63 or between 1 and 45 amino acids, more preferably of between 1 and 25 amino acids and most preferably of between 1 and 10 amino acids. If the polypeptide of the invention comprises more than one linker, each linker is independently selected from the group consisting of a covalent bond, a chemical linker and a polypeptide of preferably between 1 and 45 amino acids, more preferably of between 1 and 25 amino acids and most preferably of between 1 and 10 amino acids. If the polypeptide of the invention comprises more than one linker which is a polypeptide, it is understood that the polypeptide for each linker may differ, i.e. is selected independently of other linkers that may be present in the polypeptide of the invention. If said linker is between 1 and 10 amino acids, it is especially preferred that the linker comprises one or more glycine residues, e.g. has the amino acid sequence GGGS. If said linker is a chemical linker it is any chemical group providing a spatial distance between the two entities that are linked via the linker. That distance is preferably sufficient to allow free rotation of the two linked entities. Two polypeptides of the invention can be linked to each other for example by using a divalent aldehyde or using active esters such as disuccinimide esters (e.g. dissuccinimidyl-suberate).
[0165] In a preferred embodiment, the linker is a polypeptide having an amino acid sequence according to SEQ ID NO: 158, wherein the linker may comprise up to one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or up to fifteen single amino acid deletions, insertions and/or mutations.
[0166] In any embodiment of the polypeptide of the invention where said polypeptide comprises a first EGF-like domain selected from the group consisting of SEQ ID NO: 140-153 (i.e. SEQ ID NO: 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152 and 153) (and preferably SEQ ID NO: 147, 148, 149, 150, 151, 152 and 153) (and most preferably SEQ ID NO: 147), a linker according to SEQ ID NO: 158 and a second EGF-like domain independently selected from SEQ ID NO: 140-153 (i.e. SEQ ID NO: 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152 and 153) (and preferably SEQ ID NO: 147, 148, 149, 150, 151, 152 and 153) (and most preferably SEQ ID NO: 147), it is preferred that said first EGF-like domain, said linker and said second EGF-like domain in total may comprise up to one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or up to fifteen single amino acid deletions, insertions and/or mutations.
[0167] In any embodiment of the polypeptide of the invention where said polypeptide comprises an EGF-like domain selected from the group consisting of SEQ ID NO: 140-153 (i.e. SEQ ID NO: 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152 and 153) (and preferably SEQ ID NO: 140, 141, 142, 143, 144, 145 and 146), a linker according to SEQ ID NO: 158 and a heparin binding domain having an amino acid sequence according to any of SEQ ID NO: 154, 155, 156 or 157 (most preferably 157), it is preferred that said EGF-like domain, said linker and said heparin-binding domain in total may comprise up to one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or up to fifteen single amino acid deletions, insertions and/or mutations and more preferably may comprise up to one, two, three, four or up to five single amino acid deletions.
[0168] It is preferred that a polypeptide according to the invention specifically binds to the erbB3 receptor (SEQ ID NO: 159) and/or erbB4 receptor (SEQ ID NO: 160). As used herein, a first compound (e.g. a polypeptide or an antibody of the invention) is considered to "specifically bind" to a second compound (e.g. a receptor or an antigen), if it has a dissociation constant KD to said second compound of 100 μM or less, preferably 50 μM or less, preferably 30 μM or less, preferably 20 μM or less, preferably 10 μM or less, preferably 5 μM or less, more preferably 1 μM or less, more preferably 900 nM or less, more preferably 800 nM or less, more preferably 700 nM or less, more preferably 600 nM or less, more preferably 500 nM or less, more preferably 400 nM or less, more preferably 300 nM or less, more preferably 200 nM or less, even more preferably 100 nM or less, even more preferably 90 nM or less, even more preferably 80 nM or less, even more preferably 70 nM or less, even more preferably 60 nM or less, even more preferably 50 nM or less, even more preferably 40 nM or less, even more preferably 30 nM or less, even more preferably 20 nM or less, and even more preferably 10 nM or less and most preferably a KD of less than 1 nM. Methods to determine dissociation constants are well known to the average skilled person such as plasmon resonance, ELISA assays e.t.c.
[0169] In one preferred embodiment of the invention the polypeptide of the invention is soluble. The preferred polypeptide is soluble if it is soluble in distilled water to about 1 mg/ml, more preferably to about 10 mg/ml and most preferably to about 20 mg/ml.
[0170] In a further preferred embodiment the polypeptide of the inventions is an isolated polypeptide, which is in a further preferred embodiment also soluble as defined above.
[0171] It is also preferred that any polypeptide of the invention is able to passes the blood brain barrier, e.g. to cause a therapeutic effect when administered intravenously or via intraperitoncal injection.
[0172] Methods to test the permeability of the blood brain barrier have been outlined in the examples below.
[0173] As is shown in the examples below, neuregulin polypeptides are therapeutic agents, e.g. useful for the treatment of Parkinson's disease. As the polypeptides of the invention are considered to have improved receptor binding specificity and binding affinity, they can be administered in smaller amounts which reduces the costs of production for a therapeutically effective dosage form and further also minimizes the side-effect for the patient.
[0174] Thus, a further aspect of the invention relates to a pharmaceutical composition comprising a polypeptide of the invention.
[0175] Preferably, the pharmaceutical composition further comprising a medicament for the treatment of a neurological condition preferably a medicament selected from the group consisting of a compound affecting catecholamine metabolism, an acetylcholine esterase inhibitor, a MAO-B- or COMT-inhibitor, a memantine-type channel blocker, a dopamine or serotonine receptor agonist, a dopamine or serotonine receptor antagonist, a catecholamine or serotonine reuptake inhibitor, an antipsychotic medication, a drug for the treatments of Alzheimer's or Parkinson's disease and a medicament against schizophrenia, bipolar disorder or depression. Preferred medicaments that can be used in this context have already been mentioned above.
[0176] Yet another aspect of the invention relates to a polypeptide of the invention for use in the prophylaxis or treatment of a neurological condition. Preferably, said neurological condition is selected from the group of schizophrenia, in particular cognition-related aspects of schizophrenia, bipolar disorder and depression, Parkinson'disease; Alzheimer's disease; epilepsy; MS; ALS; stroke; traumatic brain injury and spinal chord injury. One particulary preferred use is the use to treat bipolar disorder.
[0177] Bipolar disorder (BP) is a disabling and often life-threatening disorder that affects approximately 1% of the population worldwide. Bipolar disorder (BP) is characterized by dramatic mood changes, with individuals experiencing alternating episodes of depression and mania interspersed with periods of normal function. BP is chronic, severely disabling, and life-threatening, with increased risk of suicide and estimated lifetime prevalence of ˜1%.
[0178] BP has a substantial genetic component. Monozygotic twin concordance rate estimates range from 45 to 70% and sibling recurrence risk estimates from 5 to 10.
[0179] Bipolar disorder or manic-depressive disorder, also referred to as bipolar affective disorder or manic depression, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or more depressive episodes. In this context, the elevated moods are clinically referred to as mania. In this case one differentiates between unipolar disorder (major depressive disorder) and bipolar disorder.
[0180] As was also shown in the examples, peripheral administration of a polypeptide of the invention comprising the ECD of neuregulin resulted in an increase of the total number of dopaminergic tyrosine hydroxylase (TH)+ neurons. Notably, this increase in neurons was not due to cell differentiation, as the Nrg1β1 polypeptide used was shown not to be mitogenic. Since Nrg1β1-ECD did not induce neurogenesis in the adult SNc, the newly appearing dopaminergic neurons apparently resulted from an induction of a dompaminergic phenotype in pre-existing cells. Thus, it was shown that the polypeptides of the invention function to induce cell differentiation.
[0181] Accordingly, the invention provides in a further aspect also the use of a polypeptide according to the invention or of a polynucleotide encoding said polypeptide for inducing differentiation of a cell.
[0182] As used herein "cell differentiation" or "differentiation of a cell" refers to the alteration of gene expression within a cell upon treating said cell with a differentiation factor such as a polypeptide of the invention. The altered gene expression preferably results in a phenotypic change of the cell, e.g. alteration of size (e.g. volume), shape, membrane potential, metabolic activity and/or responsiveness to signals of said cell. In a preferred embodiment cell differentiation refers to the modulation, preferably induction of a cell's ability of producing dopamine. Thus, in a particularly preferred embodiment of the use of the invention said cell produces more dopamine after having undergone cell differentiation. Most preferably the differentiated cell is at dopaminergic neuron which expresses preferably tyrosine hydroxylase (TH), e.g. can be immunostained for this protein.
[0183] In one embodiment said cell to be differentiated is a neuronal cell or a non-neuronal cell, preferably a glial cell. In this context, said neuronal or non-neuronal cell is preferably an erbB4- and/or erbB3-expressing cell. Most preferably said neuronal or non-neuronal cell is an erbB4- and/or erbB3-expressing cell that does not express neuromelanin and/or tyrosine hydroxylase.
[0184] The average skilled person can determine without undue burden, whether a cell expresses Neuromelanin or tyrosine hydroxylase e.g. by using detectably labelled antibodies which specifically bind neuromelanin and, respectively, tyrosine hydroxylase. Such antibodies can be used e.g. in an ELISA assay to quantify the aforementioned proteins as is well known in the art. A cell is considered to not express neuromelanin or tyrosine hydroxylase if no detectable amount of an antibody that is capable of specifically binding neuromelanin or tyrosine hydroxylase binds to these proteins of said cell as assessed either on a Western blot or in an ELISA assay.
[0185] In one embodiment said differentiated cell is characterized by:
[0186] (i) a decrease in expression of a protein selected from the group consisting of 14-3-3-zeta (SEQ ID NOs:58, 133), 14-3-3-epsilon (SEQ ID NOs:59, 134), and N-ethylmaleimide sensitive factor (SEQ ID NOs:50, 124) and/or
[0187] (ii) an increase in expression of a protein selected from the group consisting of Aldolase A, fructose-bisphosphate (SEQ ID NOs:2, 68); Aldolase C, fructose-bisphosphate (SEQ ID NOs:3, 69); Triosephosphate isomerase 1 (SEQ ID NOs:4, 65, 70); similar to Glyceraldehyde-3-phosphate dehydrogenaseisoform 1 (SEQ ID NOs:5, 71, 72); Enolase 1, alpha non-neuron (SEQ ID NOs:6, 73); Enolase 2, gamma neuronal (SEQ ID NOs:7, 74); Lactate dehydrogenase B (SEQ ID NOs:8, 75); Glycerol phosphate dehydrogenase 2, mitochondrial (SEQ ID NOs:9, 76, 77); Glutamate-ammonia ligase (Glutamine synthetase) (SEQ ID NOs:10, 78, 79); Dihydrolioamide S-acetyltransferase (E2 component of pyruvate dehydrogenase complex) (SEQ ID NOs:11, 80, 66); Isocitrate dehydrogenase 3 (NAD+) alpha, isoform CRA_e (SEQ ID NOs:12, 81); Malate dehydrogenase, cytoplasmic (SEQ ID NOs:13, 82); NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8 (SEQ ID NOs:14, 83); NADH dehydrogenase (ubiquinone) Fe-S protein 1 (SEQ ID NOs:15, 84, 67); NADH dehydrogenase (ubiquinone) Fe-S protein 8 (SEQ ID NOs:16, 85); Ubiquinol-cytochrome-c reductase complex core protein 1 (SEQ ID NOs:17, 86); ATP synthase H+ transporting, mitochondrial F0 complex, subunit d (SEQ ID NOs:18, 87, 88); Creatine kinase, brain (SEQ ID NOs:19, 89); Heat shock protein 8 (SEQ ID NOs:20, 90, 91); Heat shock protein 9 (SEQ ID NOs:21, 92); Hsp70 homolog perinuclear form (mortalin mot-2) (SEQ ID NO:22); Protein disulfide isomerase associated 3 (SEQ ID NOs:23, 93); ATPase, H+ transporting, lysosomal V1 subunit A (SEQ ID NOs:24, 94); Proteasome 26S subunit, ATPase, 4 (SEQ ID NOs:25, 95, 96); Proteasome subunit alpha type-2 (SEQ ID NOs:26, 97); Ubiquitin carboxy-terminal hydrolase L1, isoform CRA_b (SEQ ID NOs:27, 98); Valosin containing protein, isoform CRA_b (SEQ ID NOs:28, 99); 3-Hydroxyisobutyrate dehydrogenase (SEQ ID NOs:29, 100); Biphenyl hydrolase-like (SEQ ID NOs:30, 101); Haloacid dehalogenase-like hydrolase domain containing 2 (SEQ ID NOs:31, 102); Beta-actin (aa 27-375) (SEQ ID NOs:32, 103); Gamma-actin (SEQ ID NOs:33, 104); Profilin 2, isoform CRA_b (SEQ ID NOs:34, 105, 106); Transgelin 3 (SEQ ID NOs:35, 107); Annexin A6, isoform CRA_b (SEQ ID NOs:36, 108, 109); Internexin neuronal intermediate filament protein, alpha ((SEQ ID NOs:37, 110); Neurofilament, light polypeptide (SEQ ID NOs:38, 111); Glial fibrillary acidic protein (SEQ ID NOs:39, 112, 113); Tubulin, alpha 1B (SEQ ID NOs:40, 114); Tubulin, beta (SEQ ID NOs:41, 115); Tubulin, beta 3 (SEQ ID NOs:42, 116); Dihydropyrimidinase-like 2 (SEQ ID NOs:43, 117); Dihydropyrimidinase-like 4, isoform CRA_c (SEQ ID NOs:44, 118); Brain abundant, membrane attached signal protein 1 (SEQ ID NOs:45, 119); RAB1B, member RAS oncogene family; isoform CRA_a (SEQ ID NOs:46, 120); RAB3A, member RAS oncogene family (SEQ ID NOs:47, 121); RAB6A, member RAS oncogene family (SEQ ID NOs:48, 122); Guanosine diphosphate dissociation inhibitor 1 (SEQ ID NOs:49, 123); Phospholipase C-alpha (SEQ ID NOs:51, 125); Calcineruin B, type 1 (SEQ ID NOs:52, 126, 127); Calbindin-28K (SEQ ID NOs:53, 128); Calretinin (SEQ ID NOs:54, 129); Visinin-like 1 (SEQ ID NOs:55, 130); Chloride intracellular channel 4 (mitochondrial) (SEQ ID NOs:56, 131); mCG7191 (Raf Kinase Inhibitor Protein (RKIP)) (SEQ ID NOs:57, 132); Peroxiredoxin 1 (SEQ ID NOs:60, 135); Peroxiredoxin 3 (SEQ ID NOs:61, 136); Pyridoxal (pyridoxine, vitamin B6) kinase (SEQ ID NOs:62, 137); and Guanine nucleotide binding protein, alpha o isoform B (SEQ ID NOs:63, 138, 139).
[0188] It is to be understood that the above outlined expression changes occur following contacting said cell with a polypeptide of the invention.
[0189] In the examples of the present specification it has been shown that the extracellular domain of neuregulin1-β1 causes cell differentiation and that this domain is not mitogenic. Thus, when using a polypeptide according to the invention or a polynucleotide encoding said polypeptide for inducing differentiation of a cell according to the invention it is preferred that said polypeptide does not induce cell division but only cell differentiation. As the examples have shown this property for the extracellular domain of neuregulin which comprises the EGF-like domain as well as the heparin binding domain, it is preferred that polypeptides of the invention are used which comprises at least one, preferably at least two EGF-like domains and/or heparin-binding domains.
[0190] On the basis of the experimental evidence provided in the examples below, it is a further aspect of the invention to provide a method for producing dopaminergic neurons comprising the step a) contacting a non-neuronal cell with a neuregulin isoform of the invention and/or with a polypeptide of the invention.
[0191] Preferably said non-neuronal cell used in the method is a non-neuronal cell that does not express neuromelanin or tyrosine hydroxylast such as a cell selected from the group consisting of a glial cell, particularly an astrocyte, oligondentrocyte, an ependymal cell, a radio glial cell, a Schwann cell, a satellite cell and an enteric glia cell.
[0192] If has been found that the expression of NRG is increased in patients suffering from a neurodegenerative disease or disorder such as Alzheimer's disease, multiple sclerosis or brain damage (Cannella B, Pin D, Marchionni M, and Raine CS. Neuregulin and erbB receptor expression in normal and diseased human white matter. J Neuroimmunol 100: 233-242, 1999; Chaudhury AR, Gerecke KM, Wyss JM, Morgan DG, Gordon MN, and Carroll SL. Neuregulin-1 and erbB4 immunoreactivity is associated with neuritic plaques in Alzheimer disease brain and in a transgenic model of Alzheimer disease, J Neuropathol Exp Neurol 62: 42-54, 2003; and Tokita Y, Keino H, Matsui F, Aono S, Ishiguro H, Higashiyama S, and Oohira A. Regulation of Neuregulin Expression in the Injured Rat Brain and Cultured Astrocytes. J Neurosei 21: 1257-1264, 2001.). In line with this, the examples of the present invention show an increase in ErbB4 expression in patients suffering from Parkinson's disease.
[0193] Without being bound by theory, the increased expression of neuregulin could present the natural response of the organism to counteract the mentioned diseases. Thus, to boost the natural response, neuregulin isoforms of the invention or polypeptides of the invention can be administered to support the defensive mechanisms of the organism against the respective disease as has been outlined above.
[0194] Furthermore, the increased expression of neuregulin and its receptors erbB3 and erbB4 can provide the basis for a diagnostic method wherein the concentration of an endogenous neuregulin (e.g. neuregulin-1 and/or neuregulin-2) is measured as protein or as mRNA and then compared with the concentration found in a healthy subject. If the concentration of neuregulin protein or a polynucleotide encoding neuregulin is found to be increased this is an indication for a disease such as Parkinson's disease, Alzheimer's disease, multiple sclerosis or brain damage.
[0195] In the examples it was shown that administration of neuregulin induced a change in expression of a series of proteins in the midbrain (see in particular table 2). Thus, this expression modulation induced by neuregulin will also be diagnostic for the diseases and disorders mentioned above, which also show elevated levels of neuregulin.
[0196] Accordingly, another aspect of the invention, is an antibody capable of specifically binding to a protein selected from the group consisting of 14-3-3-zeta (SEQ ID NOs:58, 133), 14-3-3-epsilon (SEQ ID NOs:59, 134), N-ethylmaleimide sensitive factor (SEQ ID NOs:50, 124), Aldolase A, fructose-bisphosphate (SEQ ID NOs:2, 68); Aldolase C, fructose-bisphosphate (SEQ ID NOs:3, 69); Triosephosphate isomerase 1 (SEQ ID NOs:4, 65, 70); similar to Glyceraldhyde-3-phosphate Dehydrogenaseisoform 1 (SEQ ID NOs:5, 71, 72); Enolase 1, alpha non-neuron (SEQ ID NOs:6, 73); Enolase 2, gamma neuronal (SEQ ID NOs:7, 74); Lactate dehydrogenase B (SEQ ID NOs:8, 75); Glycerol phosphate dehydrogenase 2, mitochondrial (SEQ ID NOs:9, 76, 77); Glutamate-ammonia ligase (Glutamine synthethase) (SEQ ID NOs:10, 78, 79); Dihydrolipoamide S-acetyltranferase (F2 component of pyruvate dehydrogenase complex) (SEQ ID NOs:11, 80, 66); Isocitrate dehydrogenase 3 (NAD+) alpha, isoform CRA_(SEQ ID NOs:12, 81); Malate dehydrogenase, cytoplasmic (SEQ ID NOs:13, 82); NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8 (SEQ ID NOs:14, 83); NADH dehydrogenase (ubiquinone) Fe-S protein 1 (SEQ ID NOs:15, 84, 67); NADH dehydrogenase (ubiquinone) Fe-S protein 8 (SEQ ID NOs:16, 85); Ubiquinol-cytochrome-c reductase complex core protein 1 (SEQ ID NOs:17, 86); ATP synthase, H+ transporting, mitochrondrial F0 complex, subunit d (SEQ ID NOs:18, 87, 88); Creatine kinase, brain (SEQ ID NOs:19, 89); Heat shock protein 8 (SEQ ID NOs:20, 90, 91); Heat shock protein 9 (SEQ ID NOs:21, 92); Hsp70 homolog perinuclear form (mortalin mot-2) (SEQ ID NO:22); Protein disulfide isomerase associated 3 (SEQ ID NOs:23, 93); ATPase, H+ transporting, lysosomal V1 subunit A (SEQ ID NOs:24, 94); Proteasome 26S subunit, ATPase, 4 (SEQ ID NOs:25, 95, 96); Proteasome subunit alpha type-2 (SEQ ID NOs:26, 97); Ubiquitin carboxy-terminal hydrolase L1, isoform CRA_b (SEQ ID NOs:27, 98); Valosin containing protein, isoform CRA_b (SEQ ID NOs:28, 99); 3-Hydroxyisobutyrate dehydrogenase (SEQ ID NOs:29, 100); Biphenyl hydrolase-like (SEQ ID NOs:30, 101); Haloacid dehalogenase-like hydrolase domain containing 2 (SEQ ID NOs:31, 102); Beta-actin (aa 27-375)((SEQ ID NOs:32, 103); Gamma-actin (SEQ ID NOs:33, 104); Profilin 2, isoform CRA_b (SEQ ID NOs:34, 105, 106); Transgelin 3 (SEQ ID NOs:35, 107); Annexin A6, isoform CRA_b (SEQ ID NOs:36, 108, 109); Internexin neuronal intermediate filament protein, alpha (SEQ ID NOs:37, 110); Neurofilament, light polypeptide (SEQ ID NOs:38, 111); Glial fibrillary acidic protein (SEQ ID NOs:39, 112, 113); Tubulin, alpha 1B (SEQ ID NOs:40, 114); Tubulin, beta (SEQ ID NOs:41, 115); Tubulin, beta 3 (SEQ ID NOs:42, 116); Dihydropyrimidinase-like 2 (SEQ ID NOs:43, 117); Dihydropyrimidinase-like 4, isoform CRA_c (SEQ ID NOs:44, 118); Brain abundant, membrane attached signal protein 1 (SEQ ID NOs:45, 119); RAB1B, member RAS oncogene family; isoform CRA_a (SEQ ID NOs:46, 120); RAB3A, member RAS oncogene family (SEQ ID NOs:47, 121); RAB6A, member RAS oncogene family (SEQ ID NOs:48, 122); Guanosine diphosphate dissociation inhibitor 1 (SEQ ID NOs:49, 123); Phospholipase C-alpha (SEQ ID NOs:51, 125); Calcineurin B, type I (SEQ ID NOs:52, 126, 127); Calbindin-28K (SEQ ID NOs:53, 128); Calretinin (SEQ ID NOs:54, 129); Visinin-like 1 (SEQ ID NOs:55, 130); Chloride intracellular channel 4 (mitochondrial) (SEQ ID NOs:56, 131); mCG7191 (Raf Kinase Inhibitor Protein (RKIP)) (SEQ ID NOs:57, 132); Peroxiredoxin 1 (SEQ ID NOs:60, 135); Peroxiredoxin 3 (SEQ ID NOs:61, 136); Pyridoxal (pyridoxine, vitamin B6) kinase (SEQ ID NOs:62, 137); and Guanine nucleotide binding protein, alpha o isoform B (SEQ ID NOs:63, 138, 139).
[0197] for use as a diagnostic, preferably as a diagnostic for a disease selected from the group consisting of Alzheimer's disease, multiple sclerosis or brain damage and Parkinson's disease.
[0198] The term "antibody" refers to both monoclonal and polyclonal antibodies, i.e., any immunoglobulin protein or portion thereof which is capable of recognizing an antigen or hapten, i.e., the RNA cap binding domain of PB2 or a peptide thereof. Antigen-binding portions may be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. In some embodiments, antigen-binding portions include Fab, Fab', F(ab')2, Fd, Fv, dAb, and complementarily determining region (CDR) fragments, single-chain antibodies (scFv), chimeric antibodies such as humanized antibodies, diabodies, and polypeptides that contain at least a portion of an antibody that is sufficient to confer specific antigen binding to the polypeptide.
[0199] It is well known to the average skilled person of how to raise antibodies against a specific target protein once the sequence of the target protein has been identified.
[0200] A further aspect of the invention is a method of diagnosing a disease comprising
[0201] (i) determining in vitro in an isolated tissue explant or isolated body fluid of a subject the quantity of a protein having at least 90% amino acid sequence identity (preferably over the entire length of the protein selected from the group) with a protein selected from the group consisting of 14-3-3-zeta (SEQ ID NOs:58, 133); 14-3-3-epsilon (SEQ ID NOs:59, 134) N-ethylmaleimide sensitive factor (SEQ ID NOs:50, 124), Aldolase A, fructose-bisphosphate (SEQ ID NOs:2, 68); Aldolase C, fructose-bisphosphate (SEQ ID NOs:3, 69); Triosephosphate isomerase 1 (SEQ ID NOs:4, 65, 70); similar to Glyceraldhyde-3-phosphate dehydrogenaseisoform 1 (SEQ ID NOs:5, 71, 72); Enolase 1, alpha non-neuron (SEQ ID NOs:6, 73); Enolase 2, gamma neuronal (SEQ ID NOs:7, 74); Lactate dehydrogenase B (SEQ ID NOs:8, 75); Glycerol phosphate dehydrogenase 2, Mitochondrial (SEQ ID NOs:9, 76, 77); Glutamate-ammonia ligase (Glutamine synthetase) (SEQ ID NOs:10, 78, 79); Dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase complex) (SEQ ID NOs:11, 80, 66); Isocitrate dehydrogenase 3 (NAD+) alpha, isoform CRA_e (SEQ ID NOs:12, 81); Malate dehydrogenase, cytoplasmic (SEQ ID NOs:13, 82); NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 8 (SEQ ID NOs:14, 83); NADH dehydrogenase (ubiquinone) Fe-S protein 1 (SEQ ID NOs:15, 84, 67); NADH dehydrogenase (ubiquinone) Fe-S protein 8 (SEQ ID NOs:16, 85); Ubiquinol-cytochrome-c reductase complex core protein 1 (SEQ ID NOs:17, 86); ATP synthase, H+ transporting, mitochondrial F0 complex, subunit d (SEQ ID NOs:18, 87, 88); Creatine kinase, brain (SEQ ID NOs:19, 89); Heat shock protein 8 (SEQ ID NOs:20, 90, 91); Heat shock protein 9 (SEQ ID NOs:21, 92); Hsp70 homolog perinuclear form (mortalin mot-2) (SEQ ID NO:22); Protein disulfide isomerase associated 3 (SEQ ID NOs:23, 93); ATPase, H+ transporting, lysosomal V1 subunit A (SEQ ID NOs:24, 94); Proteasome 26S subunit, ATPase, 4 (SEQ ID NOs:25, 95, 96); Proteasome subunit alpha type-2 (SEQ ID NOs:26, 97); Ubiquitin carboxy-terminal hydrolase L1, isoform CRA_b (SEQ ID NOs:27, 98); Valosin containing protein, isoform CRA_b (SEQ ID NOs:28, 99); 3-Hydroxyisobutyrate dehydrogenase (SEQ ID NOs:29, 100); Biphenyl hydrolase-like (SEQ ID NOs:30, 101); Haloacid dehalogenase-like hydrolase domain containing 2 (SEQ ID NOs:31, 102); Beta-actin (aa 27-375) (SEQ ID NOs:32, 103); Gamma-actin (SEQ ID NOs:33, 104); Profilin 2, isoform CRA_b (SEQ ID NOs:34, 105, 106); Transgelin 3 (SEQ ID NOs:35, 107); Annexin A6, isoform CRA_b (SEQ ID NOs:36, 108, 109); Internexin neuronal intermediate filament protein, alpha (SEQ ID NOs:37, 110); Neurofilament, light polypeptide (SEQ ID NOs:38, 111); Glial fibrillary acidic protein (SEQ ID NOs:39, 112, 113); Tubulin, alpha 1B (SEQ ID NOs:40, 114); Tubulin, beta (SEQ ID NOs:41, 115); Tubulin, beta 3 (SEQ ID NOs:42, 116); Dihydropyrimidinase-like 2 (SEQ ID NOs:43, 117); Dihydropyrimidinase-like 4, isoform CRA_e (SEQ ID NOs:44, 118); Brain abundant, membrane attached signal protein 1 (SEQ ID NOs:45, 119); RAB1B, member RAS oncogene family; isoform CRA_a (SEQ ID NOs:46, 120); RAB3A, member RAS oncogene family (SEQ ID NOs:47, 121); RAB6A, member RAS oncogene family (SEQ ID NOs:48, 122); Guanosine diphosphate dissociation inhibitor 1 (SEQ ID NOs:49, 123); Phospholipase C-alpha (SEQ ID NOs:51, 125); Calcineurin B, type 1 (SEQ ID NOs:52, 126, 127); Calbindin-28K (SEQ ID NOs:53, 128); Calretininn (SEQ ID NOs:54, 129); Visinin-like 1 (SEQ ID NOs:55, 130); Chloride intracellular channel 4 (mitochondrial) (SEQ ID NOs:56, 131); mCG7191 (Raf Kinase Inhibitor Protein (RKIP)) (SEQ ID NOs:57, 132); Peroxiredoxin 1 (SEQ ID NOs:60, 135); Peroxiredoxin 3 (SEQ ID NOs:61, 136); Pyridoxal (pyridoxine, vitamin B6) kinase (SEQ ID NOs:62, 137); and Guanine nucleotide binding protein, alpha o isoform B (SEQ ID NOs:63, 138, 139) or a polynucleotide encoding said protein;
[0202] (ii) optionally determining whether the amount of protein differs from the amount of the same protein quantified in a healthy subject; and
[0203] (iii) optionally correlating a change in expression of said protein when compared with the expression of said protein in a healthy subject with a neurological disease which is preferably selected from the group consisting of Alzheimer's disease, multiple sclerosis or brain damage and Parkinson's disease.
[0204] An isolated tissue explant may be any tissue and preferably an isolated brain sample. As used herein "body fluid" is preferably a body fluid selected from the group consisting of cerebrospinal fluid, blood, lymph fluid, saliva and urine.
[0205] Multiple methods of quantifying proteins are known to the average skilled person from basic textbooks. Any of these methods can be used in the method of the invention. The subject, which can be a human or non-human patient suffers from a neurological disease selected from the group consisting of Alzheimer's disease, multiple sclerosis, brain damage or Parkinsons' disease if the expression of the protein or preferably at least three of the above listed proteins deviates by at least 10% from the respective expression of these proteins in an isolated tissue explant or isolated body fluid of a healthy subject, i.e. a control subject.
[0206] In a further aspect the invention also provides a polynucleotide encoding a polypeptide of the invention.
[0207] The recombinant soluble neuregulin-1 isoform of the invention or the protein of Table 2 as described herein may be administered according to any route by which effective delivery into the target tissue, e.g. the nervous systems, particularly the central nervous system, such as brain and/or spinal chord, is achieved. It was found that pharmaceutically effective concentrations of neuregulin isoforms and fragments thereof may be achieved by systemic administration. For example, the isoforms and polypeptides of the invention may be administered by injection or infusion, e.g. by intravenous injection. Particularly preferred in the context of the present invention is the intraperitoneal administration, e.g. injection. Particularly preferred in the context of the present invention is also the intracerebral administration, e.g., infusion. The isoforms and polypeptides of the invention are preferably administered in an amount of 0.1 to 5000 ng/kg body weight, particularly in an amount of 2 to 1000 ng/kg body weight and more particularly in an amount of 3 to 600 nag/kg body weight of the subject to be treated, depending on the type and severity of the condition to be treated. In other embodiments of the present invention the soluble isoform may also be administered locally, e.g. by direct administration into the central nervous system, e.g. into the spinal chord and/or into the brain. Also administration at higher dosages of up to 500 μg/kg by i.p. or s.c. Injections or infusions, or inhalation devices are may be considered. Preferably the subject to be treated is a mammal, more preferably a human patient.
[0208] It is, however, understood that depending on the severity of the disease, the type of the disease, as well as on the respective patient to be treated, e.g. the general health status of the patient, etc., different doses of the pharmaceutical according to the invention are required to elicit a therapeutic effect. The determination of the appropriate dose lies within the discretion of the attending physician.
[0209] The soluble recombinant neuregulin-1 isoforms, the protein of Table 2 as described herein and a polypeptide of the invention may be administered as a stand-alone medication, i.e. as a monotherapy or as a co-medication, i.e. in combination with a further agent, particulary with a further agent which is suitable for the treatment of a neurological condition and/or neurological disorder, preferably Parkinson's disease and bipolar disorder. Examples of further agents are compounds affecting catecholamine metabolism, acetylcholine esterase inhibitors, MAO-B- or COMT-inhibitors, Memantine-type channel blockers, dopamine or scrotonine receptor agonists or antogonists, catecholamine or serotonine reuptake inhibitors or any type of antipsychotic medicaments like clozapine or olanzapine or gabapentin-like drugs, particularly in the treatment of Alzheimer's and Parkinson's diseases, schizophrenia, bipolar disorder, depression or other neurological conditions. Additional examples of further agents are neuroprotective agents such as PARP-1 inhibitors, e.g. as disclosed in WO 2006-008118 and WO 2006/008119, which are herein incorporated by reference.
[0210] Thus, an embodiment of the present invention refers to the combination of a recombinant soluble neuregulin-1 isoform as described herein, the protein of Table 2 as described herein or a polypeptide of the invention with an agent for the treatment of psychotic disorders such as schizophrenia, bipolar disorders and depression, e.g. olanzapine or clozapine. A further embodiment refers to the combination of a recombinant soluble neuregulin-1 isoform as described herein or a polypeptide of the invention and an agent for the treatment of a neurodegenerative disease such as Parkinson's disease, Alzheimer's disease, MS or ALS. Still a further embodiment refers to the combination of a recombinant soluble neuregulin-1 isoform as described herein or a polypeptide of the invention and an agent for the treatment of epilepsy, neurological injury, such as stroke, traumatic brain injury or spinal chord injury.
[0211] The combination therapy may be effected by co-administering the recombinant soluble neuregulin-1 isoform, the protein according to table 2 or the polypeptide of the invention and said further agent in the form of a pharmaceutical composition or kit, wherein the individual agents are administered by separately or via common administration.
[0212] Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the relevant fields are intended to be covered by the present invention.
[0213] The following figures and examples are merely illustrative of the present invention and should not be construed to limit the scope of the invention as indicated by the appended claims in any way.
DESCRIPTION OF THE FIGURES
[0214] FIG. 1 ErbB4 expression in dopaminergic neurons of the substantia nigra pars compacta (SNc).
[0215] (a,b) Dopaminergic neurons in the human SNc of control persons without neurological disorders (a) and Parkinson's disease (PD) patients (b) were identified by the presence of neuromelanin (NM, brown) in the cytoplasm. The Nrg1β1-receptor ErbB4 is immunostained in black.
[0216] (c-j) Successive magnifications show details from (a) and (b); most NM-containing neurons (brown arrows) show ErbB4 immunoreactivity (black arrows) (g-j), some NM-containing neurons show no ErbB4 immunoreactivity (g,h).
[0217] (k) Some neurons in the SNc contain no NM and show strong ErbB4 immunoreactivity in cell bodies (black arrow) and processes (black arrowheads), as demonstrated here in a control person.
[0218] (l) Dopaminergic neurons in the mouse SNc were identified by their immunoreactivity for tyrosine hydroxylase (TH, red). ErbB4 is immunostained in green. The merged picture demonstrates that virtually all TH+ neurons express ErbB4 (yellow), while some ErbB4 cells in the SNc do not express TH (white arrowheads).
[0219] Scale bars (a,b), 250 μm; (c-f), 100 μm; (g-l), 50 μm.
[0220] FIG. 2 NRg1β1-ECD passes the blood-brain barrier and phosphorylates ErbB4 in healthy adult mice.
[0221] (a) [125I]-Nrg1β1-ECD levels in full blood peaked within 1 hour after a single i.p. injection and remained clearly detectable for at least 12 hours (kCPM=1000 counts per minute).
[0222] (b) [125I]-Nrg1β1-ECD penetrated 266.8% more than [131I]-BSA (bovine serum albumin) into the brain parenchyma, measured 15 minutes after a single i.p. injection. Data are counts per minute in the brain relative to blood; the BSA-uptake was set 100%. *P<0.05, two-sided t-test.
[0223] (c-c'') [125I]-Nrg1β1-ECD distribution within the brain parenchyma was studied 1 hour after a single i.p. injection, (c) shows the anatomical map of a sagittal brain section (r=rostral, c=caudal, d=dorsal, v=ventral), stained with cresyl violet (CV, blue); (c') shows the [125I]-Nrg1β1-ECD autoradiography of the same section (black); (c'') shows superimposed CV (blue) and [125I]-Nrg1β1-ECD (red) images; the strongest [125I]-Nrg1β1-ECD signal was observed in the plexus choroideus of the 4th ventricle (white arrowheads), the lateral ventricle (grey arrowheads) and the tentorium cerebelli (black arrowheads), and particularly strong [125I]-Nrg1β1-ECD signal was obtained in the piriform cortex (light blue arrowheads), the frontal cortex (dark blue arrowheads) and the ventral midbrain containing the substantia nigra (red circle).
[0224] (d) ErbB4 receptor was immunoprecipitated from frontal cortex (fCx) and striatum (Str) of mice 1 hour after a single i.p. injection of 10 μg Nrg1β1-ECD per mouse or vehicle only (NaCl). Probing the eluate with an antibody raised against phosphorylated tyrosine residues (p-Tyr) demonstrated a higher phosphorylation state after Nrg1β1-ECD-treatment compared to NaCl-treated controls.
[0225] (e) Also low doses of Nrg1β1-ECD (50 ng/kg body weight), administered i.p. once daily on 5 consecutive days, increased ErbB4 phosphorylation in the frontal cortex (fCX), striatum (Str) and SNc 1 hour after the last injection compared to vehicle (NaCl)-injections, as demonstrated by Immunochistochemistry with an antibody raised against phosphorylated ErbB4 (p-ErbB4). Quantification of the expression was done by optical density (OD) measurement; OD for NaCl was set 100%. *P<0.05, two-sided t-test.
[0226] Scale bars (c-c''), 1 min; (e), 100 μm.
[0227] FIG. 3 Peripherally administered Nrg1β1-ECD stimulates the nigrostriatal dopaminergic system in healthy adult mice.
[0228] (a) Dopamine concentrations in the ventral midbrain (vMes), ventral striatum (vStr) and dorsal striatum (dStr) were significantly elevated 7 days, but not immediately (0 days) after daily i.p. injections of Nrg1β1-ECD on 5 consecutive days. Values in NaCl-injected controls were set 100%; absolute control values were 0.8±0.1 (vMes), 12.5±2.0 (vStr) and 15.6±3.0 (dStr) ng dopamine per mg wet tissue weight. *P<0.05, ***P<0.001 vs. NaCl-injected controls; ANOVA, post hoc LSD-test.
[0229] (b,c) The absolute numbers of dopaminergic tyrosine hydroxylase (TH)+ neurons (b) and of large polygonal cresyl violet (CV)+ neurons (c) unilaterally in the substantia nigra pars compacta (SNc) were significantly increased 21 days after daily i.p.-injections of Nrg1β1-ECD on 5 consecutive days. ***P<0.001 vs. NaCl-injected controls; two-sided t-test.
[0230] (d) Confocal micrographs of 5-bromo-2'-deoxyuridine (BrdU)+ newborn cells (red) and dopaminergic TH+ neurons (green) in the SNc of mice 7 days after daily i.p.-injections of NaCl (control) or 21 days after daily i.p.-injections of Nrg1β1-ECD on 5 consecutive days. The inserts show at higher magnification the localization of BrdU and TH in separate cells.
[0231] (e) The absolute numbers of BrdU+ cells in the unilateral SNc was not significantly altered 7 or 21 days after daily i.p.-injections of Nrg1β1-ECD on 5 consecutive days, compared to NaCl-injected controls.
[0232] (f,g) Differential proteome analysis of the ventral midbrain of mice 7 days after daily i.p.-injections of Nrg1β1-ECD on 5 consecutive days demonstrated significantly altered levels of N=62 proteins compared to NaCl-treated controls (N=59 upregulated, N=3 downregulated), (f) shows the major functional categories of these proteins; %-values indicate relative numbers of proteins per group, (g,h,i) show the numbers of proteins in the three major functional groups; cytoskeleton (g), energy metabolism (h) and protein quality control (i). Abbreviations: DA, dopamine; IF, intermediate filaments; OxPhos, oxidative phosphorylation; ROS, reactive oxygen species; UPS, ubiquitin-proteasome-system.
[0233] Scale bars (d), 100 μm; (d, insert), 10 μm.
[0234] FIG. 4 Peripherally administered Nrg1β1-ECD protects the nigrostriatal dopaminergic system against 6-OHDA-induced toxicity.
[0235] Mice received an unilateral striatal 6-OHDA injection or a sham-operation and were treated i.p. with NaCl (Control) or Nrg1β1-ECD, either instantly (6 hours after 6-OHDA) or with a delay (48 hours after 6-OHDA).
[0236] (a) Amphetamine-induced body-turns towards the lesioned side were observed in 6-OHDA-lesioned animals; this pathological asymmetry was prevented, when Nrg1β1-ECD-treatment was initiated instantly, but not when initiated with delay, n.s., not significant, *P<0.05, **P<0.01, vs. Sham-NaCl; ANOVA, post hoc LSD-test.
[0237] (b) Coronal sections of the anterior forebrain of NaCl-treated or instantly Nrg1β1-ECD-treated mice were immunostained for tyrosine hydroxylase (TH) to visualize dopaminergic fibers in the striatum (left striatum; unlesioned control side; right striatum; sham-operated/6-OHDA-injected side). Note the smaller extent of the 6-OHDA-lesion in the Nrg1β1-ECD-treated compared to the NaCl-treated mouse.
[0238] (c) The optical density of TH+ dopaminergic fibers in the striatum of 6-OHDA-lesioned animals was significantly reduced on the lesioned side compared to the unlesioned control side; this pathological asymmetry was significantly attenuated, when Nrg1β1-ECD-treatment was initiated instantly, but not when initialed with delay, ***P<0.001 vs. Sham-NaCl, ###P<0.001 vs. 6-OHDA-NaCl; ANOVA, post hoc LSD-test.
[0239] (d) Coronal sections of the substantia nigra pars compacta of NaCl-treated or instantly Nrg1β1-ECD-treated mice were TH-immunostained to visualize dopaminergic neurons in the SNc of the sham-operated/6-OHDA-injected side. Note the smaller extent of the 6-OHDA-lesion in the Nrg1β1-ECD-treated as compared to the NaCl-treated mouse.
[0240] (e,f) The number of TH+ dopaminergic neurons (e) and cresyl violet+ (CV+)large neurons (f) in the SNc of 6-OHDA-lesioned animals was significantly reduced on the lesioned side as compared to the unlesioned control side; this pathological asymmetry was significantly attenuated, when Nrg1β1-ECD-treatment was initiated either instantly or with delay, ***P<0.001 vs. Sham-NaCl, ###P<0.001 vs. 6-OHDA-NaCl; ANOVA, post hoc LSD-test.
[0241] (g) All human postmitotic LUHMES neurons in vitro, as identified by immunostaining against the dopamine transporter (DAT, red) surrounding the DAPI+ nuclei (blue), expressed the ErbB4 receptor (green) in the cytoplasm. All colors are merged in the last plate.
[0242] (h,i) 6-OHDA-induced degeneration of LUHMES cells, as evidenced by a significant increase in LDH release into the culture medium (h) and in the number of pyknotic nuclei per visual field (i); pyknotic DAPI+ nuclei were identified as round chromatin clumps of irregular size (i, insert, arrowheads); both phenomena were significantly attenuated by Nrg1β1-ECD. ***P<0.001 vs. control, ##P<0.01 vs. 6-OHDA; ANOVA, post hoc LSD-test.
[0243] Scale bars (b), 2 mm; (d), 200 μm; (g,i), 10 μm.
[0244] FIG. 5 Neuregulin ECD charge plot. Shown are charges of the respective amino acids starting from the N-terminus and a polynomial extrapolation of charge over the entire region of the ECD of neuregulin. At the N-terminus there is a region of positive charges which was taken as the basis to optimize the location of the heparin binding domain (HBD)--see also SEQ ID NO:_154-157.
[0245] FIG. 6 Preferred recombinant polypeptides of the invention are shown, which are fusion proteins comprising an optimized heparin binding domain (HBD) linked over a short linker (GGGS--which is a preferred linker that can be used with any of the inventive polypeptides described herein) to an EGF-like domain of neuregulin. The fusion proteins comprise a charge-optimized HBD, are shorter than non-modified neuregulin ECD and are therapeutic polypeptides with improved target specificity and reduced mitogenic properties.
EXAMPLES
ErbB4 Expression in Human Dopaminergic Neurons in Increased in PD
[0246] We studied the expression of ErbB4 in dopaminergic neurons, identified by their neuromelanin-content in the substantia nigra pars compacta (SNc) in control persons without neurological disorders and PD patients (FIG. 1a-k).
[0247] Most neuromelanin+ neurons in the SNc of controls expressed ErbB4. The proportion of neuromelanin+ neurons expressing ErbB4 was even higher in PD (Table 1).
[0248] Interestingly, there were also some ErbB4+ cells in the SNc of controls, which lacked neuromelanin. Their proportion was also increased in PD compared to controls (Table 1).
[0249] The predominant ErbB4 expression in dopaminergic neurons and the existence of some ErbB4+ cells without dopaminergic phenotype in the SNc was verified in adult mice (FIG. 11).
[0250] These observations provide a molecular basis for functional effects of Nrg1β1 on the nigrostratal dopaminergic system.
The Entire ECD of Nrg1β1 Passes the BBB of Adult Mice
[0251] A small fragment of Nrg1β1 containing only the EGF-like domain (Thr176-Lys246 of SEQ ID NO:1, 8 kDa) passes the intact adult BBB, but interacts rather unselectively with ErbB-receptors. In contrast, the entire ECD of Nrg1β1 contains an immunoglobulin-like and heparane-sulphate binding motif to target specific neuronal sites, to strengthen specific receptor interactions and thereby to increase the biological activity. Therefore, we worked with a soluble fragment containing the entire ECD of Nrg1β1 (Nrg1β1-ECD; Ser2-Lys246 of SEQ ID NO:1; 26.9 kDa; Accession AAA58639). We used human Nrg1β1-ECD in both mouse and human experimental systems, because of a 97% amino acid sequence homology for ErbB4 between these species.
[0252] A single intraperitoneal (i.p.) injection of [125I]-Nrg1β1-ECD led to a peak concentration in blood within 1 hour and remained detectable for at least 12 hours (FIG. 2a). [125I]-Nrg1β1-ECD was found predominantly in the plasma (82.4±6.5%), only 17.6±1.4% were bound to blood cells.
[0253] [131I]-BSA (bovine serum albumin) was used as control protein, which should not readily penetrate the intact BBB. Significantly more [125I]-Nrg1β1-ECD than [131]-BSA (+266.8%, P<0.05) was detected in the brain parenchyma at 15 min after a single i.p. injection of both proteins (FIG. 2b), suggesting that the entire 26.9 kD Nrg1β1-ECD penetrated the intact adult BBB, as shown previously only for the 8 kD EGF-like fragment.
[0254] The distribution of peripherally injected [125I]-Nrg1β1-ECD within the brain parenchyma of adult mice, studied by autoradiography 1 hour after a single i.p. injection, showed clear parenchymal signals in the piriform and frontal cortex and particularly in the ventral midbrain containing the SNc (FIG. 2c) compared to [125I]-BSA-injected controls, as demonstrated previously only in neonatal mice with a smaller Nrg1β1-fragment.
Nrg1β1-ECD Leads to ErbB4-Phosphorylation in the Adult Mouse Brain
[0255] A single i.p. injection of 10 μg Nrg1β1-ECD led within 1 hours to phosphorylation of ErbB4 in the brains of adult mice, as demonstrated by immunoprecipitation of ErbB4 from the frontal cortex and striatum and probing the eluate with antibodies raised against ErbB4 and phosphorylated tyrosine-residues (FIG. 2d).
[0256] Doses as low as 50 ng/kg body weight, administered i.p. once daily on 5 consecutive days, increased ErbB4 phosphorylation in the SNc, as demonstrated by immunohistochemistry with an antibody raised against phosphorylated ErbB4 (FIG. 2e). Therefore, this treatment paradigm was used for the further experiments.
Nrg1β1-ECD Increases Dopamine Levels in the Mouse Ventral Midbrain and Striatum
[0257] Dopamine concentrations in the ventral midbrain and dorsal striatum (caudate-putamen; see Voorn, P., Vandershuren, L. J., Groenewegen, H. J., Robbins, T. W., & Pennartz, C. M. Putting a spin on the dorsal-ventral divide of the striatum. Trends Neurosci. 27, 468-474 (2004).) were significantly elevated at day 7, but not immediately (day 0) after daily i.p.-injections of Nrg1β1-ECD on 5 consecutive days (+194.7% and +136.1%, respectively; P<0.001). The effect in the ventral striatum (nucleus accumbens and olfactory tubercle; see Voorn,P. supra) was less pronounced (+63.8%; P<0.05; FIG. 3a).
Nrg1β1-ECD Increase Dopaminergic Cell Numbers in the Normal Mouse SNc
[0258] The number of dopaminergic neurons in the SNc, identified by TH-immunostaining, was significantly increased 21 days after daily i.p.-injections of Nrg1β1-ECD on 5 consecutive days (+16.7%; P<0.001; FIG. 3b).
[0259] Also the number of large polygonal cresyl violet-stained neurons with the typical morphology of dopaminergic neurons in the SNc, was increased after Nrg1β1-ECD-treatment (+21.5%; P<0.001; FIG. 3c).
Nrg1β1-ECD is not Mitogenic in the Normal Adult Mouse SNc
[0260] To determine, whether the increase in the number of nigral dopaminergic neurons results from adult neurogenesis, we injected mice once daily with thymidine analog 5-bromo-2'-deoxyuridine (BrdU) to label mitotic cells, concomitantly with the 5 day Nrg1β1-ECD-treatment.
[0261] We did not find any BrdU and TH co-localization within a single neuron in the SNc at 7 or 21 days after BrdU-injection (FIG. 3d), arguing against Nrg1β1-induced neurogenesis.
[0262] Furthermore, the absolute number of BrdU+ cells in the SNc after Nrg1β1-treatment did not increase compared to NaCl-treated controls (FIG. 3e), indicating that Nrg1β1 is not mitogenic in the normal adult mouse SNc.
Nrg1β1-ECD Induces Proteomic Changes Indicating Neuronal Differentiation in the SNc
[0263] The delayed onset of the increase in nigrostriatal dopamine (FIG. 3a) and the increased number of nigral dopaminergic neurons (FIG. 3c,d) in absence of nigral neurogenesis (FIG. 3d,e) suggests that Nrg1β1-ECD induces neuronal differentiation in the SNc. To approach the nature of this process, we performed a hypothesis-free differential proteome analysis of the ventral midbrain containing the SNc in mice 7 days after 5 consecutive days of Nrg1β1-ECD-injections compared to NaCl-injections.
[0264] N=62 proteins were significantly altered (N=3 were reduced [14-3-3-zeta, 14-3-3-epsilon and N-ethylmaleimide-sensitive Factor]; N=59 increased; supplementary Table 2 online). These proteins clustered in six functional groups (FIG. 3f):
[0265] 1.) Intracellular signaling proteins, including modulators of the ErbB-activated Raf-1 pathway (two 14-3-3 isoforms; mCG7191); phospholipase C, which is also activated downstream of ErbB and increases cytosolic Ca2+; and several Ca2+-binding and signaling proteins.
[0266] 2.) Cytoskeletal proteins implicated in actin-, intermediate filament- and microtubule networks, vesicle trafficking and axon outgrowth (FIG. 3g). The protein with the highest increase overall (+2500% vs. NaCl-controls) was dihydropyrimidinase-like 2, also known as collapsin response mediator protein 2, a Ca2+-dependent regulator of axonal outgrowth and synaptic plasticity. There was also a 100% increase in RAB3A, known to suppress toxicity in neuronal models of PD (Gitler, A. D.; Bevis, B. J.; Shorter, J.; Strathearn, K. E.; Hamamichi, S.; Su, L. J.; Caldwell, K. A.; Caldwell, G. A.; Rochet, J. C.; McCaffery, J. M.; Barlowe, C.; Lindquist, S.(2008) The Parkinson's disease protein alpha-synuclein disrupts cellular Rab homeostasis PNAS 105, 145-150).
[0267] 3.) Proteins of dopamine metabolism, namely pyridoxal kinase, an essential cofactor for aromatic-L-amino-acid decarboxylase (AADC) to convert L-dopa into dopamine, and the α-subunit of the Go1α and Go2α GTPases, optimizing vesicular filling of dopamine.
[0268] 4.) Proteins of energy metabolism including glutamine synthetase, creatine kinase, and several components of glycolysis, citrate cycle and oxidative phosphorylation (complex 1 [NADH-dehydrogenase], III [Ubiquinol-reductase] and V [ATP synthase]) (FIG. 3h).
[0269] 5.) Protein quality control components including chaperones, a lysosomal H+-transporting ATPase, proteases and ubiquitin-proteasome-system members, particularly proteasome subunits and the ubiquitin-carboxy-terminal-hydrolast-L1, mutations of which lead familial PD (FIG. 3i). The protein with the second highest increase overall (+2400% vs. NaCl-controls) was valosin-containing protein, a multifunctional protein implicated in ubiquitin-dependent proteolysis, mutations in which cause inclusion-body myopathy and frontotemporal dementia.
[0270] 6.) Antioxidants, namely peroxiredoxin 1 and 3.
[0271] Together, these data suggest that Nrg1β1-ECD modulates ErbB-downstream and Ca2+-dependent signaling cascades, induces neuronal differentiation (axon sprouting, vesicle trafficking, dopamine production and storage) and enhances 1) cellular energy production, 2) defense against oxidative stress and 3) defense against misfolded proteins.
Nrg1β1-ECD Protects Dopaminergic Mouse Neurons Against 6-Hydroxydopamine In Vivo
[0272] Since the Nrg1β1-ECD-induced proteomic changes indicate a stimulation of cellular defense systems relevant in the pathophysiology of PD, we investigated, whether Nrg1β1-ECD can protect dopaminergic neurons in an experimental PD model. We studied 6-hydroxydopamine (6-OHDA)-induced neuronal death, because this neurotoxin potently and irreversibly destroys dopaminergic neurons by 1) reducing ATP-levels, 2) inducing oxidative stress and 3) damaging proteins.
[0273] Mice received a unilateral striatal 6-OHDA injection or a sham-operation and were treated i.p. with NaCl (control) or Nrg1β1-ECD (8×50 ng/kp i.p. in 24 h-intervals). Nrg1β1-ECD-treatment started either instantly (6 h) after 6-OHDA, when first oxidative stress is generated, or with a delay (48 h), when first, yet partial, axonal and neuronal loss occurs.
[0274] Amphetamine-induced body-turns were observed 24 days after 6-OHDA injection as behavioral correlate, indicating unilateral striatal dopamine deficiency on the 6-OHDA-lesioned side. This pathological asymmetry was prevented, when Nrg1β1-ECD-treatment was initiated instantly, but not when initiated with delay (FIG. 4a).
[0275] Histological analysis 28 days after 6-OHDA injection showed consistently a reduced density of TH+ dopaminergic fibers in the 6-OHDA-lesioned striatum compared to the unlesioned side. This pathological asymmetry was also attenuated, when Nrg1β1-ECD-treatment was initiated instantly, but not when initiated with delay (FIG. 4b,c).
[0276] The number of TH+ dopaminergic neurons (FIG. 4d,e) and cresyl violet+ large polygonal neurons (FIG. 4f) in the SNc were reduced on the 6-OHDA-lesioned compared to the unlesioned side. This pathological asymmetry, however, was attenuated, when Nrg1β1-ECD-treatment was initiated either instantly or with delay (FIG. 4e,f).
[0277] It is important to notice that that protection of nigral neurons was not a mere consequence of the upregulated cell number observed in healthy controls (FIG. 3b,c), because the cell numbers were calculated as % of the individual animals' contralateral unlesioned SNc.
Nrg1β1-ECD Protects Human Dopaminergic Neurons Against 6-OHDA In Vitro
[0278] To verify, whether Nrg1β1-ECD would also protect human dopaminergic neurons, we used cultures of tetracycline-controlled, v-myc-overexpressing human mesencephalic LUHMES-cells.
[0279] Differentiated LUHMES-cells expressed the ErbB4 receptor (FIG. 4g) and were significantly protected in presence of Nrg1β1-ECD against 6-OHDA-induced degenertaion, as studied biochemically using an LDH-release assay (FIG. 4h) and microscopically by counting pyknotic nuclei (FIG. 4i).
DISCUSSION
[0280] We have shown that human Nrg1β1-ECD is soluble in serum, penetrates into the brain of healthy adult mice, induces phosphorylation of the ErbB4 receptor in the SNc, changes the proteome of the ventral midbrain in a way suggestive of neuronal and dopaminergic differentiation, increases nigrostriatal dopamine levels, activates PD-relevant molecular defense systems, and protects nigrostriatal neurons against the neurotoxin 6-OHDA. We obtained consistent results in the MPTP model (not shown). Since the degenerating dopaminergic neurons in PD strongly express ErbB4, these observations render Nrg1β1-ECD a promising candidate for symptomatic and neuroprotective therapy of PD patients.
[0281] Current therapies of PD are primarily based on dopamine replacement, providing temporary symptomatic improvement of motor symptoms. Unfortunately, patients typically develop drug-induced motor complications (dyskinesia) and no presently available therapy halts the progression of the disease in a clinically relevant manner.
[0282] Previous approaches to protect dopaminergic neurons in PD from dying with biological neurotrophic factors were compromised by their proteinaceous nature. The glial cell line-derived neurotrophic factor (GDNF) for example, one of the best studied compounds of this group, potently protects midbrain dopaminergic neurons from a variety of toxic insults (Lin, L. F., Doherty, D. H., Lile, J. D., Bektesh, S., & Collins, F. GDNF: a glial cell line-derived neurotropic factor for midbrain dopaminergic neurons. Science 260, 1130-1132 (1993)), but does not penetrate the BBB. Thus, several ways to circumvent the BBB were studied (Gill, S. S. Patel, N. K.; Hotton, G. R.; O'Sullivan, K.; McCarter, R.; Bunnage, M.; Brooks, D. J.; Svendsen, C. N.; Heywood, P. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat. Med. 9, 589-595 (2003). Kordower, J. H. Emborg, M. E.; Bloch, J.; Ma, S. Y.; Chu, Y.; Leventhal, L.; McBride, J.; Chen, E. Y.; Palfi, S.; Roitberg, B. Z.; Brown, W. D.; Holden, J. E.; Pyzalski, R.; Taylor, M. D.; Carvey, P.; Ling, Z.; Tromo, D.; Hantraye, P.; Deglon, N.; Aebischer, P. Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. Science 290, 767-773 (2000), Behrstock, S. Behrstock, S.; Ebert, A.; McHugh, J.; Vosberg, S.; Moore, J.; Schneider, B.; Capowski, E.; Hei, D.; Kordower, J.; Aebischer, P.; Svendsen, C. N.; Human neural progenitors deliver glial cell line-derived neurotrophic factor to parkinsonian rodents and aged primates. Gene Ther. 13, 379-388 (2006),), but clinical efficacy has not yet been achieved (Landg, A. E. Gill, S.; Patel, N. K.; Lozano, A.; Nutt, J. G.; Penn, R.; Brooks, D. J.; Hotton, G.; Moro, E.; Heywood, P.; Brodsky, M. A.; Burchiel, K.; Kelly, P.; Dalvi, A.; Scott, B.; Stacy, M.; Turner, D.; Wooten, V. G.; Elias, W. J.; Laws, E. R.; Dhawan, V.; Stoessl, A. J.; Matcham, J.; Coffey, R. J.; Truab, M. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann. Neurol. 59, 459-466 (2006)). These constraints apply to other known neurotophic factors as well (Thoenen, H. & Sendtner, M. Neurotrophins: from enthusiastic expectations through sobering experiences to rational therapeutic approaches. Nat. Neurosci. 5 Suppl. 1046-1050 (2002)).
[0283] In contrast, Nrg1β1-ECD acts physiologically as soluble trophic factor. An N-terminally truncated Nrg1β1-ECD fragment had already been shown to pass the immature BBB and to phosphorylate ErbB4 in neonatal mice. We have extended these findings by demonstrating that also full length Nrg1β1-ECD passes the BBB, importantly in adult animals. Upon peripheral administration, we identified radio-labeled Nrg1β1-ECD in the brain parenchyma. The distribution matched well with the pre-described expression pattern of ErbB4 and ErbB4 receptors (predominantly cerebral cortex and SNc; see Steiner, H., Blum, M., Kitai, S. T., & Fedi, P. Differential expression of ErbB3 and ErbB4 neuregulin receptors in dopamine neurons and forebrain areas of the adult rat. Exp. Neurol. 159, 494-503 (1999)). We also found biochemical and immunohistochemical evidence for phosphorylation of ErbB4 upon peripheral Nrg1β1-ECD administration. The differential proteome analysis of midbrains from Nrg1β1-ECD- vs. NaCl-treated mice identified significant changes of phopholipase C and modulators of the Raf-1 pathway, both of which are known downstream signaling components of the ErbB4 receptor. Together, these data support the view that peripherally administered Nrg1β1-ECD activated cerebral ErbB4 signaling.
[0284] In healthy adult mice, Nrg1β1-ECD increased cerebral dopamine levels. This effect was more pronounced in the dorsal (motor) striatum receiving dopaminergic afferents from the SNc than in the ventral (limbic) striatum receiving dopaminergic afferents from the ventral tegmental area. This is consistent with the previously described higher ErbB4-expression in SNc compared to the ventral tegmental area. The increased dopamine levels were not observed immediately after Nrg1β1-ECD-treatment, but only after 7 days, suggesting that structural changes rather than acute regulations underlie this phenomenon. Remarkably, Nrg1β1-ECD also increased the number of phenotypically identified dopaminergic neurons in the SNc. Since Nrg1β1-ECD did not induce neurogenesis in the adult SNc, the newly appearing dopaminergic neurons apparently resulted from an induction of a dopaminergic phenotype in pre-existing cells, most likely a subpopulation of the ErbB4+ cells in the mouse and human SNc, which did not contain TH or neuormelanin. The proteomic analysis also identified an increase in several neuronal cytoskeletal proteins, particularly such implicated in vesicle trafficking and axonal outgrowth, most strikingly collapsin response mediator protein 2. There was a significant upregulation of pyridoxal kinase, an essential cofactor of AADC in dopamine synthesis. Quinoid dihydropteridine reductase, which is part of the pathway to recycle tetrahydrobiopterin, an essential cofactor of TH, was increased by 50% (P=0.09). Finally, the α-subunit of Go-GTPases, optimizing vesicular filling of dopamine, was upregulated. These data shed light on the mechanisms, how Nrg1β1-ECD structurally strengthens the nigrostriatal dopaminergic system.
[0285] Nrg1β1-ECD also increased numerous proteins implicated in the pathophysiology of PD. Particularly, there was a significant increase in three protein components of complex 1 of the mitochondrial respiratory chain, which is considered to by dysfunctional is sporadic PD (Mizouno et al., 1989; Mizuno Y, Ohta S, Tanaka M, Takamiya S, Suzuki K, Sata T, Oya H, Ozawa T, Kagawa Y. Deficiencies in complex I subunits of the respiratory chain in Parkinson's disease. Biochem Biophys Res Commun. 1989 Sep. 29;163(3):1450-5.) Nrg1β1-ECD upregulated ubiquitin-carboxy-terminal-hydrolase-L1, responsible for the recycling of ubiquitin, which is dysfunctional in some forms of familial PD31.
[0286] In addition, Nrg1β1-ECD increased many other proteins with known functions in the defense against impaired mitochondrial energy production, protein mishandling, oxidative stress and excitotoxicity, which are considered to be the main factors causing neuronal cell death in PD (Dauer, W. & Przedborski, S. Parkinson's disease: mechanisms and models. Neuron 39, 889-909 (2003). Wood-Kaczmar, A., Gandhi, S.; Wood, N. W. (2006) Understanding the molecular causes of Parkinson's disease. Trends Mol. Med 12, 521-528). Thus, Nrg1β1-ECD appears to strengthen the midbrain neurons ideally to defend themselves against PD-related stress.
[0287] Therefore, we studied, whether Nrg1β1-ECD can protect dopaminergic neurons against 6-OHDA, as neurotoxin activating all of these pathological mechanisms (Blum, D. Torch, S.; Lambeng, N.; Nissou, M.; Benabid, A. L.; Sadoul, R.; Verna, J. M. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP; contribution to the apoptotic theory in Parkinson's disease. Prog. Neurobiol. 65, 135-172 (2001)). We used a subacute paradigm with intrastriatal 6-OHDA injection in mice, which allows to separate the temporal sequence of oxidative stress and axonal and neuronal loss (see also Alvarez-Fischer, D. et al. Characterization of the striatal 6-OHDA model of Parkinson's disease in wild type and alpha-synulein-deleted mice. Exp. Neurol. 210, 182-193 (2008). Indeed, Nrg1β1-ECD powerfully protected against 6-OHDA-induced nigral cell loss; striatal axon loss, and corresponding rotational behavior, when administered early after intoxication (i.e. when oxidative stress, but no structural damage was present--see also Alvarez-Fischer et al. supra). If Nrg1β1-ECD was administered later (i.e. when partial structural damage was already established--see also Alvarez-Fischer et al. supra), the intervention did not protect against striatal axon degeneration and corresponding rotational asymmetry, but still protected nigral neurons from retrograde degeneration.
[0288] Previous work has already described neuroprotective effects of glial growth factor-2 (a type II Nrg1)1, 2 on dopaminergic neurons in rat primary midbrain cultures against 6-OHDA (Zhang, L. Fletcher-Turner, A.: Marchionni, M. A.; Apparsundaram, S.; Lundgren, K. H.; Yurek, D. M.; Seroogy, K. B. Neurotrophic and neuroprotective effects of the neuregulin glial growth factor-2 on dopaminergic neurons in rat primary midbrain cultures. J Neurochem. 91, 1358-1368 (2004)). Our finding that Nrg1β1-ECD (a type I Nrg1)1, 2 protected human dopaminergic LUHMES neurons from 6-OHDA-induced degeneration in vitro suggests that also human midbrain dopaminergic neurons are responsive to Nrg1β1-ECD. The fact that the vast majority of neuromelanin+ dopaminergic neurons in the human SNc express ErbB4 suggests that Nrg1β1-ECD-treatment might also be effective in living human patients. The observation that a higher proportion of neuromelanin+ neurons in the SNc were ErbB4+ in PD compared to controls, may indicate that the diseased neurons in PD upregulate ErbB4-expression to seek support. An alternative interpretation may be that the subset of neuromelanin+ neurons in the SNc with ErbB4-expression might be less susceptible to degeneration in PD compared to neuromelanin+ neurons without ErbB4 expression. However, both interpretations indicate a potential benefit Nrg1β1-ECD-treatment in PD.
[0289] Nrg1β1-ECD treatment may have a dual benefit in PD. First, an increase in endogenous dopamine production may provide symptomatic relief and postpone the time until drugs with the risk of inducing motor complications (e.g. L-dopa or dopamine agonists) are required. Second, a protection of the endogenous dopaminergic neurons from degeneration may slow or even halt the progression of the disease.
TABLE-US-00008 TABLE 1 ErbB4 expression in the SNc of PD patients and controls. P Control PD % diff. (t-test) N 5 5 ±0 n.s. Gender [male:female] 3:2 3:2 ±0 n.s. Age [years] 73.3 ± 4.6 73.0 ± 2.3 -0.4 n.s. PMD [hours] 19.0 ± 5.1 19.0 ± 5.6 ±0 n.s. NM+ cells/section .sup. 462 ± 46.6 .sup. 189 ± 42.1 -59.1 <0.05 Erbb4+ (% of all 85.0 ± 5.0 94.9 ± 2.5 +11.7 <0.05 NM+ cells) Erbb4.sup.- (% of all 15.0 ± 5.0 5.1 ± 1.5 -66.0 <0.05 NM+ cells) ErbB4+ cells/section 461.8 ± 56.7 250.2 ± 40.9 -45.8 <0.05 NM.sup.- cells (% of all 14.8 ± 5.1 28.7 ± 7.2 +93.9 <0.05 ErbB4+ cells) Abbreviations: N = number; n.s. = not significant; PD = Parkinson's disease; PMD = postmortem delay (i.e. time from death to tissue fixation); NM = neuromelanin; % diff. = percent difference in PD relative to Controls.
TABLE-US-00009 TABLE 2 online: Nrg1β1-induced proteome changes in the ventral midbrain. Category Protein Accession Nr. % of control SEM (%) P-value Energy metabolism Glycolysis Aldolase A, fructose-bisphosphate gi|6671539 (SEQ ID NOs: 2, 68) 517.3 2.1965 0.0292 Aldolase C, fructose-bisphosphate gi|60687506 (SEQ ID NOs: 3, 69) 179.0 14.08 0.0249 Triosephosphate isomerase 1 gi|6678413 (SEQ ID NOs: 4, 70, 65) 164.4 13.056 0.0335 Similar to Glyceraldehyde-3-phosphate gi|149266302 (SEQ ID NOs: 5, 71, 72) 387.2 20.606 0.0049 dehydrogenaseisoform 1 Enolase 1, alpha non-neuron gi|34784434 (SEQ ID NOs: 6, 73) 295.4 11.94 0.0015 Enolase 2, gamma neuronal gi|7305027 (SEQ ID NOs: 7, 74) 223.6 11.693 0.0024 Lactate dehydrogenase B gi|6678674 (SEQ ID NOs: 8, 75) 189.7 11.418 0.0064 Glycerol phosphate dehydrogenase 2, gi|123232244 (SEQ ID NOs: 9, 76, 77) 201.1 16.154 0.0217 mitochondrial Gln synthesis Glutamate-ammonia ligase (Glutamine gi|483918 (SEQ ID NOs: 10, 78, 79) 236.1 17.296 0.0212 synthetase) Citrate cycle Dihydrolipoamide S-acetyltransferase gi|31542559 (SEQ ID NOs: 11, 80, 66) 187.0 9.7222 0.0031 (E2 component of pyruvate dehydrogenase complex) Isocitrate dehydrogenase 3 (NAD+) gi|148693875 (SEQ ID NOs: 12, 81) 232.8 11.38 0.0078 alpha, isoform CRA_e Malate dehydrogenase, cytoplasmic gi|92087001 (SEQ ID NOs: 13, 82) 162.8 9.8812 0.0112 Ox. Phos. NADH dehydrogenase (ubiquinone) 1 gi|21312012 (SEQ ID NOs: 14, 83) 457.0 alpha subcomplex, 8 NADH dehydrogenase (ubiquinone) Fe--S gi|21704020 (SEQ ID NOs: 15, 84, 67) 923.1 3.1106 0.0348 protein 1 NADH dehydrogenase (ubiquinone) Fe--S gi|46195430 (SEQ ID NOs: 16, 85) 143.0 9.6828 0.0361 protein 8 Ubiquinol-cytochrome-c reductase gi|14548301 (SEQ ID NOs: 17, 86) 235.6 15.815 0.0086 complex core protein 1 ATP synthase, H+ transporting, gi|21313679 (SEQ ID NOs: 18, 87, 88) 139.9 7.6924 0.0184 mitochondrial F0 complex, subunit d Creatine kinase Creatine kinase, brain gi|10946574 (SEQ ID NOs: 19, 89) 191.4 11.897 0.0074 Protein quality control Chaperones Heat shock protein 8 gi|42542422 (SEQ ID NOs: 20, 90, 91) 180.4 14.38 0.0258 Heat shock protein 9 gi|162461907 (SEQ ID NOs: 21, 92) 208.4 12.564 0.0055 Hsp70 homolog perinuclear form gi|435839 (SEQ ID NO: 22) 208.4 12.564 0.0055 (mortalin mot-2) Protein disulfide isomerase associated 3 gi|112293264 (SEQ ID NOs: 23, 93) 211.6 14.324 0.0163 Lysosome ATPase, H+ transporting, lysosomal V1 gi|1184659 (SEQ ID NOs: 24, 94) 208.4 12.564 0.0055 subunit A UPS Proteasome 26S subunit, ATPase, 4 gi|62201535 (SEQ ID NOs: 25, 55, 96) 302.7 16.015 0.0246 Proteasome subunit alpha type-2 gi|1709759 (SEQ ID NOs: 26, 97) 148.1 10.931 0.0405 Ubiquitin carboxy-terminal hydrolase gi|148705826 (SEQ ID NOs: 27, 98) 171.2 12.292 0.0194 L1, isoform CRA_b Valosin containing protein, isoform gi|148670554 (SEQ ID NOs: 28, 99) 2473.7 0.7808 0.0076 CRA_b Proteolysis 3-Hydroxyisobutyrate dehydrogenase gi|119507488 (SEQ ID NOs: 29, 100) 183.7 12.089 0.0107 Biphenyl hydrolase-like gi|21624609 (SEQ ID NOs: 30, 101) 201.8 17.52 0.0296 Haloacid dehalogenase-like hydrolase gi|34849757 (SEQ ID NOs: 31, 102) 145.3 9.9981 0.0349 domain containing 2 Cytoskeleton Actin network Beta-actin (aa 27-375) gi|49868 (SEQ ID NOs: 32, 103) 252.9 11.83 0.0013 Gamma-actin gi|809561 (SEQ ID NOs: 33, 104) 178.3 8.4756 0.0022 Profilin 2, isoform CRA_b gi|148703383 (SEQ ID NOs: 34, 105, 106) 157.7 13.062 0.0457 Transgelin 3 gi|9790125 (SEQ ID NOs: 35. 107) 164.0 10.753 0.0153 Annexin A6, isoform CRA_b gi|148701560 (SEQ ID NOs: 36, 108, 109) 180.4 14.38 0.0258 IF network Internexin neuronal intermediate gi|148539957 (SEQ ID NOs: 37, 110) 196.6 8.6943 0.0011 filament protein. alpha Neurofilament, light polypeptide gi|39204499 (SEQ ID NOs: 38, 111) 258.7 6.2359 0.0014 Glial fibrillary acidic protein gi|14193690 (SEQ ID NOs: 39, 112, 113) 178.8 8.219 0.0018 Microtubules Tubulin, alpha 1B gi|34740335 (SEQ ID NOs: 40, 114) 185.8 13.213 0.0148 Tubulin, beta gi|21746161 (SEQ ID NOs: 41, 115) 167.9 5.1452 0.0006 Tubulin, beta 3 gi|12963615 (SEQ ID NOs: 42, 116) 185.8 13.213 0.0148 Axon sprouting Dihydropyrimidinase-like 2 gi|40254595 (SEQ ID NOs: 43, 117) 2607.0 1.9289 0.0187 Dihydropyrimidinase-like 4, isoform gi|148685897 (SEQ ID NOs: 44, 118) 506.4 6.2263 0.0017 CRA_c Brain abundant, membrane attached gi|45598372 (SEQ ID NOs: 45, 119) 178.9 9.2437 0.0035 signal protein 1 Vesicle RAB1B, member RAS oncogene family, gi|148701156 (SEQ ID NOs: 46, 120) 263.0 18.946 0.0122 trafficing isoform CRA_a RAB3A, member RAS oncogene family gi|6679593 (SEQ ID NOs: 47, 121) 210.8 10.694 0.0022 RAB6A, member RAS oncogene family gi|13195674 (SEQ ID NOs: 48, 122) 173.9 14.361 0.0326 Guanosine diphosphate dissociation gi|33859560 (SEQ ID NOs: 49, 123) 256.1 13.667 0.0230 inhibitor 1 N-ethylmaleimide sensitive fusion gi|29789104 (SEQ ID NOs: 50, 124) 70.0 6.9797 0.0090 protein attachment protein beta Intracellular Signalling Calcium Phospholipase C-alpha gi|200397 (SEQ ID NOs: 51, 125) 211.6 14.324 0.0163 Calcineurin B, type I gi|149044720 (SEQ ID NOs: 52, 126, 127) 208.5 19.376 0.0371 Calbindin-28K gi|6753242 (SEQ ID NOs: 53, 128) 152.3 12.161 0.0467 Calretinin gi|393387 (SEQ ID NOs: 54, 129) 155.6 9.5362 0.0146 Visinin-like 1 gi|6755983 (SEQ ID NOs: 55, 130) 185.4 10.167 0.0042 Chloride Chloride intracellular channel 4 gi|7304963 (SEQ ID NOs: 56, 131) 126.8 3.8203 0.0064 (mitochondrial) Raf-1 mCG7191 (Raf Kinase Inhibitor Protein gi|148672882 (SEQ ID NOs: 57, 132) 232.9 11.347 0.0016 (RKIP)) 14-3-3-zeta gi|148676868 (SEQ ID NOs: 58, 133) 68.3 5.8498 0.0026 14-3-3-epsilon gi|148680891 (SEQ ID NOs: 59, 134) 76.5 6.1087 0.0178 ROS defense Peroxiredoxin 1 gi|6754976 (SEQ ID NOs: 60, 135) 185.1 17.832 0.0498 Peroxiredoxin 3 gi|6680690 (SEQ ID NOs: 61, 136) 165.2 10.361 0.0201 DA metabolism Pyridoxal (pyridoxine, vitamin B6) gi|26006861 (SEQ ID NOs: 62, 137) 195.6 10.171 0.0028 kinase Guanine nucleotide binding protein, gi|164607137 (SEQ ID NOs: 63, 138, 139) 215.6 12.651 0.0087 alpha o isoform B Protein levels in the ventral midbrain of Nrg1β1-treated mice were expressed as % of control values in NaCl-treated mice. Gln = glutamine, Ox. Phos = oxidative phosphorylation; UPS = ubiquitin-proteasome-system; IF = intermediate filaments; ROS = reactive oxygen species; DA = dopamine.
METHODS
Human Brains
[0290] Autopsies from pathologically confirmed PD patients and individuals without neuropsychiatric disorders were obtained from the German Brain Net (www.brain-net.net). Two formalin-fixed, paraffin-embedded, coronal, 7 μm-thick sections containing the SNc were analyzed per brain.
Animals
[0291] The experiments were approved (Regierungsprasidium Glessen; MR20/15-Nr. 84/2007, 29/2008, 68/2009, 73/2009). Male wildtype C57B16 mice (Charles River, Sulzfeld, Germany), 9-11 weeks of age were handled according to the EU Council Directive 86/609/EEC under 12 hour light-dark cycle with food and water ad libitum. Mice were sacrificed with 100 mg/kg pentobarbital i.p. and perfused transcardially with ice-cold 50 mL 0.1 M phosphate buffered saline (PBS).
Nrg1β1-ECD
[0292] Nrg1β1-ECD (377-HB/CF; R&D Systems, Minneapolis, Minn.) was dissolved at 10 ng/mL in 0.9% NaCl and injected i.p. (50 ng/kg body weight, unless indicated otherwise). Controls were saline-injected.
[125I]-Nrg1β1-ECD
[0293] Nrg1β1-ECD and BSA (Fluka, Germany) were iodinated (see e.g. Kastin, A. J., Akerstrom, V., & Pan, W. Neuregulin-1-beta1 enters brain and spinal cord by receptor-mediated transport. J Neurochem. 88, 965-970 (2004).). 5 μg Nrg1β1-ECD (0.19 nM) or BSA (74.63 pM) dissolved in 50 μL PBS (0.2 M, pH=7.5) and carrier-free Na[125I] or Na[131I] (5 μL, 0.24 μCi, Perkin Elmer) were allowed to react (3 hours, room temperature) in a freshly prepared polypropylene iodination vial with 10 μg iodogen (Sigma-Aldrich, Germany). The product was purified by HPLC (C8 column, EC 250/4 Nucleosil 300-5, Macherey-Nagel) with 0.1% trifuoroacetic acid and a gradient of increasing concentrations of 20-60% acetonitrile over 30 minutes, followed by an isocratic elution over 5 minutes and another gradient of linearly increasing concentrations of 60-100% acetonitrile over 5 minutes at a rate of 0.5 mL/min.
[125I]-Nrg1β1-ECD Blood Kinetic
[0294] N=3 mice were injected i.p. with 1.62 μCi [125I]-Nrg1β1-ECD. Radioactivity was measured in blood with a gamma counter (Cobra II, Perkin-Elmer Packard, Waltham, Mass.).
[125I]-Nrg1β1-ECD Brain Permeability
[0295] Mice were injected i.p. with 1.62 μCi [125I]-Nrg1β1-ECD and [131I]-BSA (N=5 per group) and sacrificed 1 hour later. Radioactivity of blood and the perfused brains were measured with a gamma counter (Cobra II).
[125I]-Nrg1β1-ECD Autoradiography
[0296] Mice were injected i.p. with 13.51 μCi [125I]-Nrg1β1 or [131I]-BSA (N=4 per group) and sacrificed and perfused 1 hour later. Sagittal 30 μm microtome brain sections were exposed to a BioMax MS film (Kodak, Stuttgart, Germany) for 30 days.
ErbB4 Phosphorylation
[0297] Mice were injected i.p. with 10 μg Nrg1β1-ECD or vehicle (N=4 per group) and sacrificed 1 hour Later. ErbB4 protein was affinity-purified with a rabbit polyclonal antibody (sc-283, Santa Cruz biotechnology Inc., Heidelberg, Germany) from striatum and frontal cortex. The eluate was subjected to ID-PAGE and stained with mouse monoclonal antibodies [anti-ErbB4 (sc-8050, Santa Cruz); anti-phospho-Tyrosine (4G10, Millipore, Schwalbach, Germany)].
HPLC
[0298] This ventral midbrain, the ventral striatum co. and the dorsal striatum were dissected, homogenized in 500 μl 0.4 M perchloric acid. Dopamine was measured by reversed phase ion-pair HPLC with electrochemical detection (potential 750 mV) under isocratic conditions using an Ag/AgCl reference electrode.
BrdU
[0299] Mice were injected i.p. with 50 mg BrdU (Sigma; 5 mg/mL in 0.9% NaCl) per kg body weight and 1 hour later with 50 ng Nrg1β1 per kg body weight and sacrificed 7 or 21 days later (N=5 per group).
Differential Proteome Analysis
[0300] Mice were injected i.p. once daily for 5 consecutive days with 50 ng Nrg1β1-ECD per kg body weight or 0.9% NaCl and sacrificed 7 days after the last injection (N=5 per group). The ventral midbrain was dissected. Samples were thawed at 25° C., dissolved in 8 M Urea/4% CHAPS/0.1 M Tris (pH 7.4), and iodinated with [125I] or [131I] at identical iodine concentrations. Equal amounts of protein (<5 μg) from a [125I]- and a [131I]-labeled sample were mixed and separated by high resolution 2D-PAGE high resolution `daisy chains` covering a pH range of 4-9 (see e.g. Poznanovic, S., Schwall, G., Zengerling, H., & Cahill, M. A. Isoelectric focusing in serial immobilized pH gradient gels to improve protein separation in proteomic analysis. Electrophoresis 26, 3185-3190 (2005)). Quantitative differential displays of the [125I]- and [131I]-signals of proteins from Nrg1β1-ECD- and NaCl-samples were generated using a sensitive radio-imaging technique (see e.g. Groehe, K. et al. Differential proteomic profiling of mitochondria from Podospora anserina, rat and human reveals distinct patterns of age-related oxidative changes. Exp. Gerontol, 42, 887-898 (2007)). Protein spots with significantly different intensities between the Nrg1β1-ECD- and NaCl-groups were determined (GREG software, www.fit.fraunhofer.de), excised from the 2D-PAGE-gels (ProPick robot, Genomic Solutions Ltd., Huntingdon, UK), cleaved by trypsin (ProGest robot, Genomic Solutions Ltd.), and applied onto an anchor target (ProMS robot, Genomic Solutions Ltd.). Mass spectra of peptide ions were obtained with an Ultraflex MALDI time-of-flight (TOF) mass spectrometer (Bruker, Bremen, Germany) in reflector mode within a mass range from mlz 800 to 4000 (see e.g. Groebe, K. et al. supra). Peptide mass fingerprints were searched against the non-redundant NCBI Protein Sequence Database (Mascot server software, Matrix Science, London, UK).
6-OHDA In Vivo
[0301] 6-OHDA (Sigma: 5 μg in 2 μL 0.9% NaCl with 0.2 μg/μL ascorbic acid) was injected slowly (0.5 μL/min) into the striatum (coordinates: AP +0.9 mm, ML -1.8 mm, DV -3.0 mm relative to bregma and dura) of anesthetized mice (1% ketamine/0.2% xylazine, 10 ml/kg body weight); controls were vehicle-injected (sham-OP). Mice received 50 ng Nrg1β1-ECD per kg body weight once daily at noon for 8 consecutive days starting instantly (6 h) or delayed (48 h) after 6-OHDA injection; controls were saline-injected. Mice were sacrificed 28 days after 6-OHDA injection (N=10-12 per group).
Amphetamine-Induced Rotation
[0302] Four days prior to sacrifice, all mice received 5 mg d-amphetamine (Sigma) per kg body weight i.p.. Rotational behavior was monitored for 30 minutes (Viewer II, rotation plug-in. Biobserve, Bonn, Germany). Total net 360° body turns per minute were calculated; positive values indicate Rotations ipsilateral to the lesioned side.
6-OHDA In Vitro
[0303] LUHMES cells were proliferated and differentiated as described (Lotharius,J. Falsig, J.; van, Beck J.; Payne, S.; Dringen, R.; Brundin, P.; Leist, M. Progressive degeneration of human mesencephalic neuron-derived cells triggered by dopamine-dependent oxidative stress is dependent on the mixed-lineage kinase pathway. J. Neurosci. 25, 6329-6342 (2005)). Differentiated cells were treated with or without 100 ng Nrg1β1 per mL medium and intoxicated 1 hours later for 48 hours with 32 μM 6-OHDA.
LDH Release
[0304] LDH levels in the culture medium were measured from at least 12 wells per condition from three independent experiments using the CytoTox-ONE®Homogeneous Membrane Integrity Assay (Promega, Mannheim, Germany).
Immunohistochemistry
[0305] Mounted human sections, free-floating mouse sections or cultures were stained with the following antibodies: rabbit polyclonal anti-TH (P40101-0, Pel-Freez Biologicals, Rogers, AR; 1/1000), rat polyclonal anti-DAT (MAB369, Chemicon International, Temecula, Calif.; 1/1000), rat polyclonal anti-BrdU (OBT0030CX, Immunologicals Direct, Oxfordshire, UK; 1/500), rabbit polyclonal anti-ErbB4 (sc-283, Santa Cruz Biotechnology, Santa Cruz, Calif.; 1/200), rabbit polyclonal anti-Y1284-phosphorylated-ErbB4 (ab61059, Abcam, Cambridge, UK; 1/200).
Image Analysis
[0306] All neuromelanin-containing neurons in the human SNc per section were analyzed to determine their number and percentage of ErbB4 expression by brightfield microscopy (DM-RB, Leica, Wetzlar, Germany; SimplePCI 6.1 software; Hamamatsu Photonics, Herrsching, Germany). Double-immunofluorescence was analyzed by confocal microscopy (Leitz TCS SP5, Leica; MetaMorph software, Molecular Devices, Munich, Germany). Unbiased sterological estimations of total cell numbers were determined on every 5th serial section over the entire rostro-caudal extension of the mouse SNc (-2.4 to -4.1 mm from bregma) using the optical fractionator method (Microphot FX, Olympus, Hamburg, Germany; Stereoinvestigator software, MicroBrightField, Magdeburg, Germany). The optical density of TH+ fibers was quantified at 8 equally spaced sections in the striatum (1.7 to -0.5 mm from bregma) under bright-field illumination (eVision Copylizer, Kayser Fototechnik, Buchen, Germany; Imagel v1.42 software, NIH, Bethesda, Md.) and corrected for background in adjacent white matter. The optical density of p-ErbB4-immunoreactivity was measured identically in anatomically matched sections in frontal cortex (+1.7 mm from bregma), striatum (+1.0 mm) and SNc (-3.0 mm). Pyknotic DAPI° nuclei in cultures, identified as round chromatin clumps of irregular sixe, were counted in ten randomly distributed visual fields per culture well (DM-IRB; Leica; SimplePCI 6.1. Hamamatsu).
Statistics
[0307] Data are shown as mean ±s.e.m. Normal, parametric data were compared with the two-sided, unpaired t-test or ANOVA followed by post-hoc Fisher least significant difference (LSD) test. P<0.05 was considered significant.
Sequence CWU
1
1
1601645PRTHomo sapiens 1Met Ser Glu Arg Lys Glu Gly Arg Gly Lys Gly Lys
Gly Lys Lys Lys 1 5 10
15 Glu Arg Gly Ser Gly Lys Lys Pro Glu Ser Ala Ala Gly Ser Gln Ser
20 25 30 Pro Ala Leu
Pro Pro Gln Leu Lys Glu Met Lys Ser Gln Glu Ser Ala 35
40 45 Ala Gly Ser Lys Leu Val Leu Arg
Cys Glu Thr Ser Ser Glu Tyr Ser 50 55
60 Ser Leu Arg Phe Lys Trp Phe Lys Asn Gly Asn Glu Leu
Asn Arg Lys 65 70 75
80 Asn Lys Pro Gln Asn Ile Lys Ile Gln Lys Lys Pro Gly Lys Ser Glu
85 90 95 Leu Arg Ile Asn
Lys Ala Ser Leu Ala Asp Ser Gly Glu Tyr Met Cys 100
105 110 Lys Val Ile Ser Lys Leu Gly Asn Asp
Ser Ala Ser Ala Asn Ile Thr 115 120
125 Ile Val Glu Ser Asn Glu Ile Ile Thr Gly Met Pro Ala Ser
Thr Glu 130 135 140
Gly Ala Tyr Val Ser Ser Glu Ser Pro Ile Arg Ile Ser Val Ser Thr 145
150 155 160 Glu Gly Ala Asn Thr
Ser Ser Ser Thr Ser Thr Ser Thr Thr Gly Thr 165
170 175 Ser His Leu Val Lys Cys Ala Glu Lys Glu
Lys Thr Phe Cys Val Asn 180 185
190 Gly Gly Glu Cys Phe Met Val Lys Asp Leu Ser Asn Pro Ser Arg
Tyr 195 200 205 Leu
Cys Lys Cys Pro Asn Glu Phe Thr Gly Asp Arg Cys Gln Asn Tyr 210
215 220 Val Met Ala Ser Phe Tyr
Lys His Leu Gly Ile Glu Phe Met Glu Ala 225 230
235 240 Glu Glu Leu Tyr Gln Lys Arg Val Leu Thr Ile
Thr Gly Ile Cys Ile 245 250
255 Ala Leu Leu Val Val Gly Ile Met Cys Val Val Ala Tyr Cys Lys Thr
260 265 270 Lys Lys
Gln Arg Lys Lys Leu His Asp Arg Leu Arg Gln Ser Leu Arg 275
280 285 Ser Glu Arg Asn Asn Met Met
Asn Ile Ala Asn Gly Pro His His Pro 290 295
300 Asn Pro Pro Pro Glu Asn Val Gln Leu Val Asn Gln
Tyr Val Ser Lys 305 310 315
320 Asn Val Ile Ser Ser Glu His Ile Val Glu Arg Glu Ala Glu Thr Ser
325 330 335 Phe Ser Thr
Ser His Tyr Thr Ser Thr Ala His His Ser Thr Thr Val 340
345 350 Thr Gln Thr Pro Ser His Ser Trp
Ser Asn Gly His Thr Glu Ser Ile 355 360
365 Leu Ser Glu Ser His Ser Val Ile Val Met Ser Ser Val
Glu Asn Ser 370 375 380
Arg His Ser Ser Pro Thr Gly Gly Pro Arg Gly Arg Leu Asn Gly Thr 385
390 395 400 Gly Gly Pro Arg
Glu Cys Asn Ser Phe Leu Arg His Ala Arg Glu Thr 405
410 415 Pro Asp Ser Tyr Arg Asp Ser Pro His
Ser Glu Arg Tyr Val Ser Ala 420 425
430 Met Thr Thr Pro Ala Arg Met Ser Pro Val Asp Phe His Thr
Pro Ser 435 440 445
Ser Pro Lys Ser Pro Pro Ser Glu Met Ser Pro Pro Val Ser Ser Met 450
455 460 Thr Val Ser Met Pro
Ser Met Ala Val Ser Pro Phe Met Glu Glu Glu 465 470
475 480 Arg Pro Leu Leu Leu Val Thr Pro Pro Arg
Leu Arg Glu Lys Lys Phe 485 490
495 Asp His His Pro Gln Gln Phe Ser Ser Phe His His Asn Pro Ala
His 500 505 510 Asp
Ser Asn Ser Leu Pro Ala Ser Pro Leu Arg Ile Val Glu Asp Glu 515
520 525 Glu Tyr Glu Thr Thr Gln
Glu Tyr Glu Pro Ala Gln Glu Pro Val Lys 530 535
540 Lys Leu Ala Asn Ser Arg Arg Ala Lys Arg Thr
Lys Pro Asn Gly His 545 550 555
560 Ile Ala Asn Arg Leu Glu Val Asp Ser Asn Thr Ser Ser Gln Ser Ser
565 570 575 Asn Ser
Glu Ser Glu Thr Glu Asp Glu Arg Val Gly Glu Asp Thr Pro 580
585 590 Phe Leu Gly Ile Gln Asn Pro
Leu Ala Ala Ser Leu Glu Ala Thr Pro 595 600
605 Ala Phe Arg Leu Ala Asp Ser Arg Thr Asn Pro Ala
Gly Arg Phe Ser 610 615 620
Thr Gln Glu Glu Ile Gln Ala Arg Leu Ser Ser Val Ile Ala Asn Gln 625
630 635 640 Asp Pro Ile
Ala Val 645 2364PRTMus musculus 2Met Pro His Pro Tyr Pro
Ala Leu Thr Pro Glu Gln Lys Lys Glu Leu 1 5
10 15 Ser Asp Ile Ala His Arg Ile Val Ala Pro Gly
Lys Gly Ile Leu Ala 20 25
30 Ala Asp Glu Ser Thr Gly Ser Ile Ala Lys Arg Leu Gln Ser Ile
Gly 35 40 45 Thr
Glu Asn Thr Glu Glu Asn Arg Arg Phe Tyr Arg Gln Leu Leu Leu 50
55 60 Thr Ala Asp Asp Arg Val
Asn Pro Cys Ile Gly Gly Val Ile Leu Phe 65 70
75 80 His Glu Thr Leu Tyr Gln Lys Ala Asp Asp Gly
Arg Pro Phe Pro Gln 85 90
95 Val Ile Lys Ser Lys Gly Gly Val Val Gly Ile Lys Val Asp Lys Gly
100 105 110 Val Val
Pro Leu Ala Gly Thr Asn Gly Glu Thr Thr Thr Gln Gly Leu 115
120 125 Asp Gly Leu Ser Glu Arg Cys
Ala Gln Tyr Lys Lys Asp Gly Ala Asp 130 135
140 Phe Ala Lys Trp Arg Cys Val Leu Lys Ile Gly Glu
His Thr Pro Ser 145 150 155
160 Ala Leu Ala Ile Met Glu Asn Ala Asn Val Leu Ala Arg Tyr Ala Ser
165 170 175 Ile Cys Gln
Gln Asn Gly Ile Val Pro Ile Val Glu Pro Glu Ile Leu 180
185 190 Pro Asp Gly Asp His Asp Leu Lys
Arg Cys Gln Tyr Val Thr Glu Lys 195 200
205 Val Leu Ala Ala Val Tyr Lys Ala Leu Ser Asp His His
Val Tyr Leu 210 215 220
Glu Gly Thr Leu Leu Lys Pro Asn Met Val Thr Pro Gly His Ala Cys 225
230 235 240 Thr Gln Lys Phe
Ser Asn Glu Glu Ile Ala Met Ala Thr Val Thr Ala 245
250 255 Leu Arg Arg Thr Val Pro Pro Ala Val
Thr Gly Val Thr Phe Leu Ser 260 265
270 Gly Gly Gln Ser Glu Glu Glu Ala Ser Ile Asn Leu Asn Ala
Ile Asn 275 280 285
Lys Cys Pro Leu Leu Lys Pro Trp Ala Leu Thr Phe Ser Tyr Gly Arg 290
295 300 Ala Leu Gln Ala Ser
Ala Leu Lys Ala Trp Gly Gly Lys Lys Glu Asn 305 310
315 320 Leu Lys Ala Ala Gln Glu Glu Tyr Ile Lys
Arg Ala Leu Ala Asn Ser 325 330
335 Leu Ala Cys Gln Gly Lys Tyr Thr Pro Ser Gly Gln Ser Gly Ala
Ala 340 345 350 Ala
Ser Glu Ser Leu Phe Ile Ser Asn His Ala Tyr 355
360 3363PRTMus musculus 3Met Pro His Ser Tyr Pro Ala Leu
Ser Ala Glu Gln Lys Lys Glu Leu 1 5 10
15 Ser Asp Ile Ala Leu Arg Ile Val Thr Pro Gly Lys Gly
Ile Leu Ala 20 25 30
Ala Asp Glu Ser Val Gly Ser Met Ala Lys Arg Leu Ser Gln Ile Gly
35 40 45 Val Glu Asn Thr
Glu Glu Asn Arg Arg Leu Tyr Arg Gln Val Leu Phe 50
55 60 Ser Ala Asp Asp Arg Val Lys Lys
Cys Ile Gly Gly Val Ile Phe Phe 65 70
75 80 His Glu Thr Leu Tyr Gln Lys Asp Asp Asn Gly Val
Pro Phe Val Arg 85 90
95 Thr Ile Gln Asp Lys Gly Ile Leu Val Gly Ile Lys Val Asp Lys Gly
100 105 110 Val Val Pro
Leu Ala Gly Thr Asp Gly Glu Thr Thr Thr Gln Gly Leu 115
120 125 Asp Gly Leu Leu Glu Arg Cys Ala
Gln Tyr Lys Lys Asp Gly Ala Asp 130 135
140 Phe Ala Lys Trp Arg Cys Val Leu Lys Ile Ser Asp Arg
Thr Pro Ser 145 150 155
160 Ala Leu Ala Ile Leu Glu Asn Ala Asn Val Leu Ala Arg Tyr Ala Ser
165 170 175 Ile Cys Gln Gln
Asn Gly Ile Val Pro Ile Val Glu Pro Glu Ile Leu 180
185 190 Pro Asp Gly Asp His Asp Leu Lys Arg
Cys Gln Tyr Val Thr Glu Lys 195 200
205 Val Leu Ala Ala Val Tyr Lys Ala Leu Ser Asp His His Val
Tyr Leu 210 215 220
Glu Gly Thr Leu Leu Lys Pro Asn Met Val Thr Pro Gly His Ala Cys 225
230 235 240 Pro Ile Lys Tyr Ser
Pro Glu Glu Ile Ala Met Ala Thr Val Thr Ala 245
250 255 Leu Arg Arg Thr Val Pro Pro Ala Val Pro
Gly Val Thr Phe Leu Ser 260 265
270 Gly Gly Gln Ser Glu Glu Glu Ala Ser Leu Asn Leu Asn Ala Ile
Asn 275 280 285 Arg
Cys Pro Leu Pro Arg Pro Trp Ala Leu Thr Phe Ser Tyr Gly Arg 290
295 300 Ala Leu Gln Ala Ser Ala
Leu Asn Ala Trp Arg Gly Gln Arg Asp Asn 305 310
315 320 Ala Gly Ala Ala Thr Glu Glu Phe Ile Lys Arg
Ala Glu Met Asn Gly 325 330
335 Leu Ala Ala Gln Gly Arg Tyr Glu Gly Ser Gly Asp Gly Gly Ala Ala
340 345 350 Ala Gln
Ser Leu Tyr Ile Ala Asn His Ala Tyr 355 360
4249PRTMus musculus 4Met Ala Pro Thr Arg Lys Phe Phe Val Gly Gly
Asn Trp Lys Met Asn 1 5 10
15 Gly Arg Lys Lys Cys Leu Gly Glu Leu Ile Cys Thr Leu Asn Ala Ala
20 25 30 Asn Val
Pro Ala Gly Thr Glu Val Val Cys Ala Pro Pro Thr Ala Tyr 35
40 45 Ile Asp Phe Ala Arg Gln Lys
Leu Asp Pro Lys Ile Ala Val Ala Ala 50 55
60 Gln Asn Cys Tyr Lys Val Thr Asn Gly Ala Phe Thr
Gly Glu Ile Ser 65 70 75
80 Pro Gly Met Ile Lys Asp Leu Gly Ala Thr Trp Val Val Leu Gly His
85 90 95 Ser Glu Arg
Arg His Val Phe Gly Glu Ser Asp Glu Leu Ile Gly Gln 100
105 110 Lys Val Ser His Ala Leu Ala Glu
Gly Leu Gly Val Ile Ala Cys Ile 115 120
125 Gly Glu Lys Leu Asp Glu Arg Glu Ala Gly Ile Thr Glu
Lys Val Val 130 135 140
Phe Glu Gln Thr Lys Val Ile Ala Asp Asn Val Lys Asp Trp Ser Lys 145
150 155 160 Val Val Leu Ala
Tyr Glu Pro Val Trp Ala Ile Gly Thr Gly Lys Thr 165
170 175 Ala Thr Pro Gln Gln Ala Gln Glu Val
His Glu Lys Leu Arg Gly Trp 180 185
190 Leu Lys Ser Asn Val Asn Asp Gly Val Ala Gln Ser Thr Arg
Ile Ile 195 200 205
Tyr Gly Gly Ser Val Thr Gly Ala Thr Cys Lys Glu Leu Ala Ser Gln 210
215 220 Pro Asp Val Asp Gly
Phe Leu Val Gly Gly Ala Ser Leu Lys Pro Glu 225 230
235 240 Phe Val Asp Ile Ile Asn Ala Lys Gln
245 5333PRTMus musculus 5 Met Val Lys Val Gly
Val Asn Gly Phe Gly Arg Ile Gly His Leu Val 1 5
10 15 Thr Arg Ala Ala Ile Cys Ser Gly Lys Val
Glu Ile Val Ala Ile Asn 20 25
30 Asp Pro Phe Ile Asp Leu Asn Tyr Met Val Tyr Met Phe Gln Tyr
Asp 35 40 45 Ser
Thr His Gly Lys Phe Asn Gly Thr Val Lys Ala Glu Asn Gly Lys 50
55 60 Leu Val Ile Asn Gly Lys
Pro Ile Thr Ile Phe Gln Glu Arg Asp Pro 65 70
75 80 Thr Asn Ile Lys Trp Gly Glu Ala Gly Ala Glu
Tyr Val Val Glu Ser 85 90
95 Thr Gly Val Phe Thr Ile Met Glu Lys Ala Gly Ala His Leu Lys Gly
100 105 110 Gly Ala
Lys Arg Val Ile Ile Ser Ala Pro Ser Ala Asp Ala Pro Met 115
120 125 Phe Val Met Gly Val Asn His
Glu Lys Tyr Asp Asn Ser Leu Lys Ile 130 135
140 Val Asn Asn Ala Ser Cys Thr Thr Asn Cys Leu Ala
Pro Leu Ser Lys 145 150 155
160 Val Ile His Asp Asn Phe Gly Ile Val Glu Gly Leu Met Thr Thr Val
165 170 175 His Ala Ile
Thr Ala Thr Gln Lys Thr Val Gly Gly Pro Ser Gly Lys 180
185 190 Leu Trp Arg Asp Gly Arg Gly Ala
Ala Gln Asn Ile Ile Pro Ala Ser 195 200
205 Thr Gly Ala Ala Lys Ala Val Gly Lys Val Ile Pro Glu
Leu Asn Gly 210 215 220
Lys Leu Thr Gly Met Ala Phe Arg Val Pro Thr Pro Asn Val Ser Val 225
230 235 240 Val Asp Leu Thr
Cys Arg Leu Glu Lys Pro Ala Lys Tyr Asp Asp Ile 245
250 255 Lys Lys Val Val Lys Gln Ala Ser Glu
Gly Pro Leu Lys Gly Ile Leu 260 265
270 Gly Tyr Thr Glu Asp Gln Val Val Ser Cys Asp Phe Asn Ser
Asn Ser 275 280 285
His Ser Ser Thr Phe Asp Ala Gly Ala Val Ile Ala Leu Asn Asp Asn 290
295 300 Phe Val Lys Leu Ile
Ser Trp Tyr Asp Asn Glu Tyr Gly Tyr Ser Asn 305 310
315 320 Arg Val Val Asp Leu Met Ala Tyr Met Ala
Ser Lys Glu 325 330
6366PRTMus musculus 6 Met Leu Ser Leu Ser Pro His Phe Leu Ser Leu Gln Lys
Val Asn Val 1 5 10 15
Val Glu Gln Glu Lys Ile Asp Lys Leu Met Ile Glu Met Asp Gly Thr
20 25 30 Glu Asn Lys Ser
Lys Phe Gly Ala Asn Ala Ile Leu Gly Val Ser Leu 35
40 45 Ala Val Cys Lys Ala Gly Ala Val Glu
Lys Gly Val Pro Leu Tyr Arg 50 55
60 His Ile Ala Asp Leu Ala Gly Asn Pro Glu Val Ile Leu
Pro Val Pro 65 70 75
80 Ala Phe Asn Val Ile Asn Gly Gly Ser His Ala Gly Asn Lys Leu Ala
85 90 95 Met Gln Glu Phe
Met Ile Leu Pro Val Gly Ala Ser Ser Phe Arg Glu 100
105 110 Ala Met Arg Ile Gly Ala Glu Val Tyr
His Asn Leu Lys Asn Val Ile 115 120
125 Lys Glu Lys Tyr Gly Lys Asp Ala Thr Asn Val Gly Asp Glu
Gly Gly 130 135 140
Phe Ala Pro Asn Ile Leu Glu Asn Lys Glu Ala Leu Glu Leu Leu Lys 145
150 155 160 Thr Ala Ile Ala Lys
Ala Gly Tyr Thr Asp Gln Val Val Ile Gly Met 165
170 175 Asp Val Ala Ala Ser Glu Phe Tyr Arg Ser
Gly Lys Tyr Asp Leu Asp 180 185
190 Phe Lys Ser Pro Asp Asp Pro Ser Arg Tyr Ile Thr Pro Asp Gln
Leu 195 200 205 Ala
Asp Leu Tyr Lys Ser Phe Val Gln Asn Tyr Pro Val Val Ser Ile 210
215 220 Glu Asp Pro Phe Asp Gln
Asp Asp Trp Gly Ala Trp Gln Lys Phe Thr 225 230
235 240 Ala Ser Ala Gly Ile Gln Val Val Gly Asp Asp
Leu Thr Val Thr Asn 245 250
255 Pro Lys Arg Ile Ala Lys Ala Ala Ser Glu Lys Ser Cys Asn Cys Leu
260 265 270 Leu Leu
Lys Val Asn Gln Ile Gly Ser Val Thr Glu Ser Leu Gln Ala 275
280 285 Cys Lys Leu Ala Gln Ser Asn
Gly Trp Gly Val Met Val Ser His Arg 290 295
300 Ser Gly Glu Thr Glu Asp Thr Phe Ile Ala Asp Leu
Val Val Gly Leu 305 310 315
320 Cys Thr Gly Gln Ile Lys Thr Gly Ala Pro Cys Arg Ser Glu Arg Leu
325 330 335 Ala Lys Tyr
Asn Gln Ile Leu Arg Ile Glu Glu Glu Leu Gly Ser Lys 340
345 350 Ala Lys Phe Ala Gly Arg Ser Phe
Arg Asn Pro Leu Ala Lys 355 360
365 7434PRTMus musculus 7Met Ser Ile Glu Lys Ile Trp Ala Arg Glu Ile
Leu Asp Ser Arg Gly 1 5 10
15 Asn Pro Thr Val Glu Val Asp Leu Tyr Thr Ala Lys Gly Leu Phe Arg
20 25 30 Ala Ala
Val Pro Ser Gly Ala Ser Thr Gly Ile Tyr Glu Ala Leu Glu 35
40 45 Leu Arg Asp Gly Asp Lys Gln
Arg Tyr Leu Gly Lys Gly Val Leu Lys 50 55
60 Ala Val Asp His Ile Asn Ser Arg Ile Ala Pro Ala
Leu Ile Ser Ser 65 70 75
80 Gly Ile Ser Val Val Glu Gln Glu Lys Leu Asp Asn Leu Met Leu Glu
85 90 95 Leu Asp Gly
Thr Glu Asn Lys Ser Lys Phe Gly Ala Asn Ala Ile Leu 100
105 110 Gly Val Ser Leu Ala Val Cys Lys
Ala Gly Ala Ala Glu Arg Asp Leu 115 120
125 Pro Leu Tyr Arg His Ile Ala Gln Leu Ala Gly Asn Ser
Asp Leu Ile 130 135 140
Leu Pro Val Pro Ala Phe Asn Val Ile Asn Gly Gly Ser His Ala Gly 145
150 155 160 Asn Lys Leu Ala
Met Gln Glu Phe Met Ile Leu Pro Val Gly Ala Glu 165
170 175 Ser Phe Arg Asp Ala Met Arg Leu Gly
Ala Glu Val Tyr His Thr Leu 180 185
190 Lys Gly Val Ile Lys Asp Lys Tyr Gly Lys Asp Ala Thr Asn
Val Gly 195 200 205
Asp Glu Gly Gly Phe Ala Pro Asn Ile Leu Glu Asn Ser Glu Ala Leu 210
215 220 Glu Leu Val Lys Glu
Ala Ile Asp Lys Ala Gly Tyr Thr Glu Lys Met 225 230
235 240 Val Ile Gly Met Asp Val Ala Ala Ser Glu
Phe Tyr Arg Asp Gly Lys 245 250
255 Tyr Asp Leu Asp Phe Lys Ser Pro Ala Asp Pro Ser Arg Tyr Ile
Thr 260 265 270 Gly
Asp Gln Leu Gly Ala Leu Tyr Gln Asp Phe Val Arg Asn Tyr Pro 275
280 285 Val Val Ser Ile Glu Asp
Pro Phe Asp Gln Asp Asp Trp Ala Ala Trp 290 295
300 Ser Lys Phe Thr Ala Asn Val Gly Ile Gln Ile
Val Gly Asp Asp Leu 305 310 315
320 Thr Val Thr Asn Pro Lys Arg Ile Glu Arg Ala Val Glu Glu Lys Ala
325 330 335 Cys Asn
Cys Leu Leu Leu Lys Val Asn Gln Ile Gly Ser Val Thr Glu 340
345 350 Ala Ile Gln Ala Cys Lys Leu
Ala Gln Glu Asn Gly Trp Gly Val Met 355 360
365 Val Ser His Arg Ser Gly Glu Thr Glu Asp Thr Phe
Ile Ala Asp Leu 370 375 380
Val Val Gly Leu Cys Thr Gly Gln Ile Lys Thr Gly Ala Pro Cys Arg 385
390 395 400 Ser Glu Arg
Leu Ala Lys Tyr Asn Gln Leu Met Arg Ile Glu Glu Glu 405
410 415 Leu Gly Asp Glu Ala Arg Phe Ala
Gly His Asn Phe Arg Asn Pro Ser 420 425
430 Val Leu 8334PRTMus musculus 8Met Ala Thr Leu Lys
Glu Lys Leu Ile Ala Ser Val Ala Asp Asp Glu 1 5
10 15 Ala Ala Val Pro Asn Asn Lys Ile Thr Val
Val Gly Val Gly Gln Val 20 25
30 Gly Met Ala Cys Ala Ile Ser Ile Leu Gly Lys Ser Leu Ala Asp
Glu 35 40 45 Leu
Ala Leu Val Asp Val Leu Glu Asp Lys Leu Lys Gly Glu Met Met 50
55 60 Asp Leu Gln His Gly Ser
Leu Phe Leu Gln Thr Pro Lys Ile Val Ala 65 70
75 80 Asp Lys Asp Tyr Ser Val Thr Ala Asn Ser Lys
Ile Val Val Val Thr 85 90
95 Ala Gly Val Arg Gln Gln Glu Gly Glu Ser Arg Leu Asn Leu Val Gln
100 105 110 Arg Asn
Val Asn Val Phe Lys Phe Ile Ile Pro Gln Ile Val Lys Tyr 115
120 125 Ser Pro Asp Cys Thr Ile Ile
Val Val Ser Asn Pro Val Asp Ile Leu 130 135
140 Thr Tyr Val Thr Trp Lys Leu Ser Gly Leu Pro Lys
His Arg Val Ile 145 150 155
160 Gly Ser Gly Cys Asn Leu Asp Ser Ala Arg Phe Arg Tyr Leu Met Ala
165 170 175 Glu Lys Leu
Gly Ile His Pro Ser Ser Cys His Gly Trp Ile Leu Gly 180
185 190 Glu His Gly Asp Ser Ser Val Ala
Val Trp Ser Gly Val Asn Val Ala 195 200
205 Gly Val Ser Leu Gln Glu Leu Asn Pro Glu Met Gly Thr
Asp Asn Asp 210 215 220
Ser Glu Asn Trp Lys Glu Val His Lys Met Val Val Asp Ser Ala Tyr 225
230 235 240 Glu Val Ile Lys
Leu Lys Gly Tyr Thr Asn Trp Ala Ile Gly Leu Ser 245
250 255 Val Ala Asp Leu Ile Glu Ser Met Leu
Lys Asn Leu Ser Arg Ile His 260 265
270 Pro Val Ser Thr Met Val Lys Gly Met Tyr Gly Ile Glu Asn
Glu Val 275 280 285
Phe Leu Ser Leu Pro Cys Ile Leu Asn Ala Arg Gly Leu Thr Ser Val 290
295 300 Ile Asn Gln Lys Leu
Lys Asp Asp Glu Val Ala Gln Leu Arg Lys Ser 305 310
315 320 Ala Asp Thr Leu Trp Asp Ile Gln Lys Asp
Leu Lys Asp Leu 325 330
9745PRTMus musculus 9 Met Ala Phe Gln Lys Ala Val Lys Gly Thr Ile Leu Val
Gly Gly Gly 1 5 10 15
Ala Leu Ala Thr Val Leu Gly Leu Ser Pro Phe Ala His Tyr Arg Arg
20 25 30 Lys Gln Val Ser
Leu Ala Tyr Val Glu Ala Ala Gly Tyr Leu Thr Glu 35
40 45 Pro Val Asn Arg Glu Pro Pro Ser Arg
Glu Ala Gln Leu Met Thr Leu 50 55
60 Lys Asn Thr Pro Glu Phe Asp Ile Leu Val Ile Gly Gly
Gly Ala Thr 65 70 75
80 Gly Cys Gly Cys Ala Leu Asp Ala Val Thr Arg Gly Leu Lys Thr Ala
85 90 95 Leu Val Glu Arg
Asp Asp Phe Ser Ser Gly Thr Ser Ser Arg Ser Thr 100
105 110 Lys Leu Ile His Gly Gly Val Arg Tyr
Leu Gln Lys Ala Ile Met Asn 115 120
125 Leu Asp Val Glu Gln Tyr Arg Met Val Lys Glu Ala Leu His
Glu Arg 130 135 140
Ala Asn Leu Leu Glu Ile Ala Pro His Leu Ser Ala Pro Leu Pro Ile 145
150 155 160 Met Leu Pro Leu Tyr
Lys Trp Trp Gln Leu Pro Tyr Tyr Trp Val Gly 165
170 175 Ile Lys Met Tyr Asp Leu Val Ala Gly Ser
Gln Cys Leu Lys Ser Ser 180 185
190 Tyr Val Leu Ser Lys Ser Arg Ala Leu Glu His Phe Pro Met Leu
Gln 195 200 205 Lys
Asp Lys Leu Val Gly Ala Ile Val Tyr Tyr Asp Gly Gln His Asn 210
215 220 Asp Ala Arg Met Asn Leu
Ala Ile Ala Leu Thr Ala Ala Arg Tyr Gly 225 230
235 240 Ala Ala Thr Ala Asn Tyr Met Glu Val Val Ser
Leu Leu Lys Lys Thr 245 250
255 Asp Pro Glu Thr Gly Lys Glu Arg Val Ser Gly Ala Arg Cys Lys Asp
260 265 270 Val Leu
Thr Gly Gln Glu Phe Asp Val Arg Ala Lys Cys Val Ile Asn 275
280 285 Ala Ser Gly Pro Phe Thr Asp
Ser Val Arg Lys Met Asp Asp Lys Asn 290 295
300 Val Val Pro Ile Cys Gln Pro Ser Ala Gly Val His
Ile Val Met Pro 305 310 315
320 Gly Tyr Tyr Ser Pro Glu Asn Met Gly Leu Leu Asp Pro Ala Thr Ser
325 330 335 Asp Gly Arg
Val Ile Phe Phe Leu Pro Trp Glu Lys Met Thr Ile Ala 340
345 350 Gly Thr Thr Asp Thr Pro Thr Asp
Val Thr His His Pro Ile Pro Ser 355 360
365 Glu Glu Asp Ile Asn Phe Ile Leu Asn Glu Val Arg Asn
Tyr Leu Ser 370 375 380
Ser Asp Val Glu Val Arg Arg Gly Asp Val Leu Ala Ala Trp Ser Gly 385
390 395 400 Ile Arg Pro Leu
Val Thr Asp Pro Lys Ser Ala Asp Thr Gln Ser Ile 405
410 415 Ser Arg Asn His Val Val Asp Ile Ser
Asp Ser Gly Leu Ile Thr Ile 420 425
430 Ala Gly Gly Lys Trp Thr Thr Tyr Arg Ser Met Ala Glu Asp
Thr Val 435 440 445
Asp Ala Ala Val Lys Phe His Asn Leu Asn Ala Gly Pro Ser Arg Thr 450
455 460 Val Gly Leu Phe Leu
Gln Gly Gly Lys Asp Trp Ser Pro Thr Leu Tyr 465 470
475 480 Ile Arg Leu Val Gln Asp Tyr Gly Leu Glu
Ser Glu Val Ala Gln His 485 490
495 Leu Ala Lys Thr Tyr Gly Asp Lys Ala Phe Glu Val Ala Lys Met
Ala 500 505 510 Ser
Val Thr Gly Lys Arg Trp Pro Val Val Gly Val Arg Leu Val Ser 515
520 525 Glu Phe Pro Tyr Ile Glu
Ala Glu Val Lys Tyr Gly Ile Lys Glu Tyr 530 535
540 Ala Cys Thr Ala Val Asp Met Ile Ser Arg Arg
Thr Arg Leu Ala Phe 545 550 555
560 Leu Asn Val Gln Ala Ala Glu Glu Ala Leu Pro Arg Ile Val Glu Leu
565 570 575 Met Gly
Arg Glu Leu Asn Trp Ser Glu Leu Arg Lys Gln Cys Val Thr 580
585 590 Tyr Asp Ser Asp Gly Ser Thr
Val Ala Thr Ser Trp Ser Ser Gln Glu 595 600
605 Glu Leu Glu Thr Ala Thr Arg Phe Leu Tyr Tyr Glu
Met Gly Tyr Lys 610 615 620
Ser Arg Thr Glu Gln Leu Thr Asp Ser Thr Glu Ile Ser Leu Leu Pro 625
630 635 640 Ser Asp Ile
Asp Arg Tyr Lys Lys Arg Phe His Lys Phe Asp Glu Asp 645
650 655 Glu Lys Gly Phe Ile Thr Ile Val
Asp Val Gln Arg Val Leu Glu Ser 660 665
670 Ile Asn Val Gln Met Asp Glu Asn Thr Leu His Glu Ile
Leu Cys Glu 675 680 685
Val Asp Leu Asn Lys Asn Gly Gln Val Glu Leu His Glu Phe Leu Gln 690
695 700 Leu Met Ser Ala
Val Gln Lys Gly Arg Val Ser Gly Ser Arg Leu Ala 705 710
715 720 Ile Leu Met Lys Thr Ala Glu Glu Asn
Leu Asp Arg Arg Val Pro Ile 725 730
735 Pro Val Asp Arg Ser Cys Gly Gly Leu 740
745 10373PRTMus musculus 10Met Ala Thr Ser Ala Ser Ser His
Leu Asn Lys Gly Ile Lys Gln Met 1 5 10
15 Tyr Met Ser Leu Pro Gln Gly Glu Lys Val Gln Ala Met
Tyr Ile Trp 20 25 30
Val Asp Gly Thr Gly Glu Gly Leu Arg Cys Lys Thr Arg Thr Leu Asp
35 40 45 Cys Glu Pro Lys
Cys Val Glu Glu Leu Pro Glu Trp Asn Phe Asp Gly 50
55 60 Ser Ser Thr Phe Gln Ser Glu Gly
Ser Asn Ser Asp Met Tyr Leu His 65 70
75 80 Pro Val Ala Met Phe Arg Asp Pro Phe Arg Lys Asp
Pro Asn Lys Leu 85 90
95 Val Leu Cys Glu Val Phe Lys Tyr Asn Arg Lys Pro Ala Glu Ser Asn
100 105 110 Leu Arg His
Ile Cys Lys Arg Ile Met Asp Met Val Ser Asn Gln His 115
120 125 Pro Trp Phe Gly Met Glu Gln Glu
Tyr Thr Leu Met Gly Thr Asp Gly 130 135
140 His Pro Phe Gly Trp Pro Ser Asn Gly Phe Pro Gly Pro
Gln Gly Pro 145 150 155
160 Tyr Tyr Cys Gly Val Gly Ala Asp Lys Ala Tyr Gly Arg Asp Ile Val
165 170 175 Glu Ala His Tyr
Arg Ala Cys Leu Tyr Ala Gly Val Lys Ile Thr Gly 180
185 190 Thr Asn Ala Glu Val Met Pro Ala Gln
Trp Glu Phe Gln Ile Gly Pro 195 200
205 Cys Glu Gly Ile Arg Met Gly Asp His Leu Trp Ile Ala Arg
Phe Ile 210 215 220
Leu His Arg Val Cys Glu Asp Phe Gly Val Ile Ala Thr Phe Asp Pro 225
230 235 240 Lys Pro Ile Pro Gly
Asn Trp Asn Gly Ala Gly Cys His Thr Asn Phe 245
250 255 Ser Thr Lys Ala Met Arg Glu Glu Asn Gly
Leu Lys Trp Ile Glu Glu 260 265
270 Ala Ile Asp Lys Leu Ser Lys Arg His Gln Tyr His Ile Arg Ala
Tyr 275 280 285 Asp
Pro Lys Gly Gly Leu Asp Asn Ala Arg Arg Leu Thr Gly Phe His 290
295 300 Glu Thr Ser Asn Ile Asn
Asp Phe Ser Ala Gly Val Ala Asn Arg Gly 305 310
315 320 Ala Ser Ile Arg Ile Pro Arg Thr Val Gly Gln
Glu Lys Lys Gly Tyr 325 330
335 Phe Glu Asp Arg Arg Pro Ser Ala Asn Cys Asp Pro Tyr Ala Val Thr
340 345 350 Glu Ala
Ile Val Arg Thr Cys Leu Leu Asn Glu Thr Gly Asp Glu Pro 355
360 365 Phe Gln Tyr Lys Asn 370
11642PRTMus musculus 11Met Trp Arg Val Cys Ala Arg Arg Ala
Arg Ser Ala Val Pro Arg Asp 1 5 10
15 Gly Phe Arg Ala Arg Trp Ala Ala Leu Lys Glu Gly Pro Gly
Ala Pro 20 25 30
Cys Gly Ser Pro Arg Ile Gly Pro Ala Ala Val Arg Cys Gly Ser Gly
35 40 45 Ile Pro Arg Tyr
Gly Val Arg Ser Leu Cys Gly Trp Ser Ser Gly Ser 50
55 60 Gly Thr Val Pro Arg Asn Arg Leu
Leu Arg Gln Leu Leu Gly Ser Pro 65 70
75 80 Ser Arg Arg Ser Tyr Ser Leu Pro Pro His Gln Lys
Val Pro Leu Pro 85 90
95 Ser Leu Ser Pro Thr Met Gln Ala Gly Thr Ile Ala Arg Trp Glu Lys
100 105 110 Lys Glu Gly
Glu Lys Ile Ser Glu Gly Asp Leu Ile Ala Glu Val Glu 115
120 125 Thr Asp Lys Ala Thr Val Gly Phe
Glu Ser Leu Glu Glu Cys Tyr Met 130 135
140 Ala Lys Ile Leu Val Pro Glu Gly Thr Arg Asp Val Pro
Val Gly Ser 145 150 155
160 Ile Ile Cys Ile Thr Val Glu Lys Pro Gln Asp Ile Glu Ala Phe Lys
165 170 175 Asn Tyr Thr Leu
Asp Leu Ala Ala Ala Ala Ala Pro Gln Ala Ala Pro 180
185 190 Ala Ala Ala Pro Ala Thr Ala Ala Ala
Pro Ala Ala Pro Ser Ala Ser 195 200
205 Ala Pro Gly Ser Ser Tyr Pro Thr His Met Gln Ile Val Leu
Pro Ala 210 215 220
Leu Ser Pro Thr Met Thr Met Gly Thr Val Gln Arg Trp Glu Lys Lys 225
230 235 240 Val Gly Glu Lys Leu
Ser Glu Gly Asp Leu Leu Ala Glu Ile Glu Thr 245
250 255 Asp Lys Ala Thr Ile Gly Phe Glu Val Gln
Glu Glu Gly Tyr Leu Ala 260 265
270 Lys Ile Leu Val Pro Glu Gly Thr Arg Asp Val Pro Leu Gly Ala
Pro 275 280 285 Leu
Cys Ile Ile Val Glu Lys Gln Glu Asp Ile Ala Ala Phe Ala Asp 290
295 300 Tyr Arg Pro Thr Glu Val
Thr Ser Leu Lys Pro Gln Ala Ala Pro Pro 305 310
315 320 Ala Pro Pro Pro Val Ala Ala Val Pro Pro Thr
Pro Gln Pro Val Ala 325 330
335 Pro Thr Pro Ser Ala Ala Pro Ala Gly Pro Lys Gly Arg Val Phe Val
340 345 350 Ser Pro
Leu Ala Lys Lys Leu Ala Ala Glu Lys Gly Ile Asp Leu Thr 355
360 365 Gln Val Lys Gly Thr Gly Pro
Glu Gly Arg Ile Ile Lys Lys Asp Ile 370 375
380 Asp Ser Phe Val Pro Ser Lys Ala Ala Pro Ala Ala
Ala Ala Ala Met 385 390 395
400 Ala Pro Pro Gly Pro Arg Val Ala Pro Ala Pro Ala Gly Val Phe Thr
405 410 415 Asp Ile Pro
Ile Ser Asn Ile Arg Arg Val Ile Ala Gln Arg Leu Met 420
425 430 Gln Ser Lys Gln Thr Ile Pro His
Tyr Tyr Leu Ser Val Asp Val Asn 435 440
445 Met Gly Glu Val Leu Leu Val Arg Lys Glu Leu Asn Lys
Met Leu Glu 450 455 460
Gly Lys Gly Lys Ile Ser Val Asn Asp Phe Ile Ile Lys Ala Ser Ala 465
470 475 480 Leu Ala Cys Leu
Lys Val Pro Glu Ala Asn Ser Ser Trp Met Asp Thr 485
490 495 Val Ile Arg Gln Asn His Val Val Asp
Val Ser Val Ala Val Ser Thr 500 505
510 Pro Ala Gly Leu Ile Thr Pro Ile Val Phe Asn Ala His Ile
Lys Gly 515 520 525
Leu Glu Thr Ile Ala Ser Asp Val Val Ser Leu Ala Ser Lys Ala Arg 530
535 540 Glu Gly Lys Leu Gln
Pro His Glu Phe Gln Gly Gly Thr Phe Thr Ile 545 550
555 560 Ser Asn Leu Gly Met Phe Gly Ile Lys Asn
Phe Ser Ala Ile Ile Asn 565 570
575 Pro Pro Gln Ala Cys Ile Leu Ala Ile Gly Ala Ser Glu Asp Lys
Leu 580 585 590 Ile
Pro Ala Asp Asn Glu Lys Gly Phe Asp Val Ala Ser Val Met Ser 595
600 605 Val Thr Leu Ser Cys Asp
His Arg Val Val Asp Gly Ala Val Gly Ala 610 615
620 Gln Trp Leu Ala Glu Phe Lys Lys Tyr Leu Glu
Lys Pro Ile Thr Met 625 630 635
640 Leu Leu 12316PRTMus musculus 12Met Lys Ile Phe Asp Ala Ala Lys
Ala Pro Ile Gln Trp Glu Glu Arg 1 5 10
15 Asn Val Thr Ala Ile Gln Gly Pro Gly Gly Lys Trp Met
Ile Pro Pro 20 25 30
Glu Ala Lys Glu Ser Met Asp Lys Asn Lys Met Gly Leu Lys Gly Pro
35 40 45 Leu Lys Thr Pro
Ile Ala Ala Gly His Pro Ser Met Asn Leu Leu Leu 50
55 60 Arg Lys Thr Phe Asp Leu Tyr Ala
Asn Val Arg Pro Cys Val Ser Ile 65 70
75 80 Glu Gly Tyr Lys Thr Pro Tyr Thr Asp Val Asn Ile
Val Thr Ile Arg 85 90
95 Glu Asn Thr Glu Gly Glu Tyr Ser Gly Ile Glu His Val Ile Val Asp
100 105 110 Gly Val Val
Gln Ser Ile Lys Leu Ile Thr Glu Glu Ala Ser Lys Arg 115
120 125 Ile Ala Glu Phe Ala Phe Glu Tyr
Ala Arg Asn Asn His Arg Ser Asn 130 135
140 Val Thr Ala Val His Lys Ala Asn Ile Met Arg Met Ser
Asp Gly Leu 145 150 155
160 Phe Leu Gln Lys Cys Arg Glu Val Ala Glu Asn Cys Lys Asp Ile Lys
165 170 175 Phe Asn Glu Met
Tyr Leu Asp Thr Val Cys Leu Asn Met Val Gln Asp 180
185 190 Pro Ser Gln Phe Asp Val Leu Val Met
Pro Asn Leu Tyr Gly Asp Ile 195 200
205 Leu Ser Asp Leu Cys Ala Gly Leu Ile Gly Gly Leu Gly Val
Thr Pro 210 215 220
Ser Gly Asn Ile Gly Ala Asn Gly Val Ala Ile Phe Glu Ser Val His 225
230 235 240 Gly Thr Ala Pro Asp
Ile Ala Gly Lys Asp Met Ala Asn Pro Thr Ala 245
250 255 Leu Leu Leu Ser Ala Val Met Met Leu Arg
His Met Gly Leu Phe Asp 260 265
270 His Ala Ala Lys Ile Glu Ala Ala Cys Phe Ala Thr Ile Lys Asp
Gly 275 280 285 Lys
Ser Leu Thr Lys Asp Leu Gly Gly Asn Ala Lys Cys Ser Asp Phe 290
295 300 Thr Glu Glu Ile Cys Arg
Arg Val Lys Asp Leu Asp 305 310 315
13334PRTMus musculus 13Met Ser Glu Pro Ile Arg Val Leu Val Thr Gly Ala
Ala Gly Gln Ile 1 5 10
15 Ala Tyr Ser Leu Leu Tyr Ser Ile Gly Asn Gly Ser Val Phe Gly Lys
20 25 30 Asp Gln Pro
Ile Ile Leu Val Leu Leu Asp Ile Thr Pro Met Met Gly 35
40 45 Val Leu Asp Gly Val Leu Met Glu
Leu Gln Asp Cys Ala Leu Pro Leu 50 55
60 Leu Gln Asp Val Ile Ala Thr Asp Lys Glu Glu Ile Ala
Phe Lys Asp 65 70 75
80 Leu Asp Val Ala Val Leu Val Gly Ser Met Pro Arg Arg Glu Gly Met
85 90 95 Glu Arg Lys Asp
Leu Leu Lys Ala Asn Val Lys Ile Phe Lys Ser Gln 100
105 110 Gly Thr Ala Leu Glu Lys Tyr Ala Lys
Lys Ser Val Lys Val Ile Val 115 120
125 Val Gly Asn Pro Ala Asn Thr Asn Cys Leu Thr Ala Ser Lys
Ser Ala 130 135 140
Pro Ser Ile Pro Lys Glu Asn Phe Ser Cys Leu Thr Arg Leu Asp His 145
150 155 160 Asn Arg Ala Lys Ser
Gln Ile Ala Leu Lys Leu Gly Val Thr Ala Asp 165
170 175 Asp Val Lys Asn Val Ile Ile Trp Gly Asn
His Ser Ser Thr Gln Tyr 180 185
190 Pro Asp Val Asn His Ala Lys Val Lys Leu Gln Gly Lys Glu Val
Gly 195 200 205 Val
Tyr Glu Ala Leu Lys Asp Asp Ser Trp Leu Lys Gly Glu Phe Ile 210
215 220 Thr Thr Val Gln Gln Arg
Gly Ala Ala Val Ile Lys Ala Arg Lys Leu 225 230
235 240 Ser Ser Ala Met Ser Ala Ala Lys Ala Ile Ala
Asp His Ile Arg Asp 245 250
255 Ile Trp Phe Gly Thr Pro Glu Gly Glu Phe Val Ser Met Gly Val Ile
260 265 270 Ser Asp
Gly Asn Ser Tyr Gly Val Pro Asp Asp Leu Leu Tyr Ser Phe 275
280 285 Pro Val Val Ile Lys Asn Lys
Thr Trp Lys Phe Val Glu Gly Leu Pro 290 295
300 Ile Asn Asp Phe Ser Arg Glu Lys Met Asp Leu Thr
Ala Lys Glu Leu 305 310 315
320 Thr Glu Glu Lys Glu Thr Ala Phe Glu Phe Leu Ser Ser Ala
325 330 14172PRTMus musculus 14 Met
Pro Gly Ile Val Glu Leu Pro Thr Leu Glu Glu Leu Lys Val Glu 1
5 10 15 Glu Val Lys Val Ser Ser
Ala Val Leu Lys Ala Ala Ala His His Tyr 20
25 30 Gly Ala Gln Cys Asp Lys Thr Asn Lys Glu
Phe Met Leu Cys Arg Trp 35 40
45 Glu Glu Lys Asp Pro Arg Arg Cys Leu Lys Glu Gly Lys Leu
Val Asn 50 55 60
Gly Cys Ala Leu Asn Phe Phe Arg Gln Ile Lys Ser His Cys Ala Glu 65
70 75 80 Pro Phe Thr Glu Tyr
Trp Thr Cys Leu Asp Tyr Ser Asn Met Gln Leu 85
90 95 Phe Arg His Cys Arg Gln Gln Gln Ala Lys
Phe Asp Gln Cys Val Leu 100 105
110 Asp Lys Leu Gly Trp Val Arg Pro Asp Leu Gly Gln Leu Ser Lys
Val 115 120 125 Thr
Lys Val Lys Thr Asp Arg Pro Leu Pro Glu Asn Pro Tyr His Ser 130
135 140 Arg Ala Arg Pro Glu Pro
Asn Pro Val Ile Glu Gly Asp Leu Lys Pro 145 150
155 160 Ala Lys His Gly Thr Arg Phe Phe Phe Trp Thr
Val 165 170 15727PRTMus musculus
15 Met Leu Arg Ile Pro Ile Lys Arg Ala Leu Ile Gly Leu Ser Asn Ser 1
5 10 15 Pro Lys Gly Tyr
Val Arg Thr Thr Gly Thr Ala Ala Ser Asn Leu Ile 20
25 30 Glu Val Phe Val Asp Gly Gln Ser Val
Met Val Glu Pro Gly Thr Thr 35 40
45 Val Leu Gln Ala Cys Glu Lys Val Gly Met Gln Ile Pro Arg
Phe Cys 50 55 60
Tyr His Glu Arg Leu Ser Val Ala Gly Asn Cys Arg Met Cys Leu Val 65
70 75 80 Glu Ile Glu Lys Ala
Pro Lys Val Val Ala Ala Cys Ala Met Pro Val 85
90 95 Met Lys Gly Trp Asn Ile Leu Thr Asn Ser
Glu Lys Ser Lys Lys Ala 100 105
110 Arg Glu Gly Val Met Glu Phe Leu Leu Ala Asn His Pro Leu Asp
Cys 115 120 125 Pro
Ile Cys Asp Gln Gly Gly Glu Cys Asp Leu Gln Asp Gln Ser Met 130
135 140 Met Phe Gly Ser Asp Arg
Ser Arg Phe Leu Glu Gly Lys Arg Ala Val 145 150
155 160 Glu Asp Lys Asn Ile Gly Pro Leu Val Lys Thr
Ile Met Thr Arg Cys 165 170
175 Ile Gln Cys Thr Arg Cys Ile Arg Phe Ala Ser Glu Ile Ala Gly Val
180 185 190 Asp Asp
Leu Gly Thr Thr Gly Arg Gly Asn Asp Met Gln Val Gly Thr 195
200 205 Tyr Ile Glu Lys Met Phe Met
Ser Glu Leu Ser Gly Asn Val Ile Asp 210 215
220 Ile Cys Pro Val Gly Ala Leu Thr Ser Lys Pro Tyr
Ala Phe Thr Ala 225 230 235
240 Arg Pro Trp Glu Thr Arg Lys Thr Glu Ser Ile Asp Val Met Asp Ala
245 250 255 Val Gly Ser
Asn Ile Val Val Ser Thr Arg Thr Gly Glu Val Met Arg 260
265 270 Ile Leu Pro Arg Met His Glu Asp
Ile Asn Glu Glu Trp Ile Ser Asp 275 280
285 Lys Thr Arg Phe Ala Tyr Asp Gly Leu Lys Arg Gln Arg
Leu Thr Glu 290 295 300
Pro Met Val Arg Asn Glu Lys Gly Leu Leu Thr Tyr Thr Ser Trp Glu 305
310 315 320 Asp Ala Leu Ser
Arg Val Ala Gly Met Leu Gln Asn Phe Glu Gly Asn 325
330 335 Ala Val Ala Ala Ile Ala Gly Gly Leu
Val Asp Ala Glu Ala Leu Val 340 345
350 Ala Leu Lys Asp Leu Leu Asn Lys Val Asp Ser Asp Asn Leu
Cys Thr 355 360 365
Glu Glu Ile Phe Pro Thr Glu Gly Ala Gly Thr Asp Leu Arg Ser Asn 370
375 380 Tyr Leu Leu Asn Thr
Thr Ile Ala Gly Val Glu Glu Ala Asp Val Val 385 390
395 400 Leu Leu Val Gly Thr Asn Pro Arg Phe Glu
Ala Pro Leu Phe Asn Ala 405 410
415 Arg Ile Arg Lys Ser Trp Leu His Asn Asp Leu Lys Val Ala Leu
Ile 420 425 430 Gly
Ser Pro Val Asp Leu Thr Tyr Arg Tyr Asp His Leu Gly Asp Ser 435
440 445 Pro Lys Ile Leu Gln Asp
Ile Ala Ser Gly Arg His Ser Phe Cys Glu 450 455
460 Val Leu Lys Asp Ala Lys Lys Pro Met Val Val
Leu Gly Ser Ser Ala 465 470 475
480 Leu Gln Arg Asp Asp Gly Ala Ala Ile Leu Ala Ala Val Ser Asn Met
485 490 495 Val Gln
Lys Ile Arg Val Thr Thr Gly Val Ala Ala Glu Trp Lys Val 500
505 510 Met Asn Ile Leu His Arg Ile
Ala Ser Gln Val Ala Ala Leu Asp Leu 515 520
525 Gly Tyr Lys Pro Gly Val Glu Ala Ile Arg Lys Asn
Pro Pro Lys Met 530 535 540
Leu Phe Leu Leu Gly Ala Asp Gly Gly Cys Ile Thr Arg Gln Asp Leu 545
550 555 560 Pro Lys Asp
Cys Phe Ile Val Tyr Gln Gly His His Gly Asp Val Gly 565
570 575 Ala Pro Met Ala Asp Val Ile Leu
Pro Gly Ala Ala Tyr Thr Glu Lys 580 585
590 Ser Ala Thr Tyr Val Asn Thr Glu Gly Arg Ala Gln Gln
Thr Lys Val 595 600 605
Ala Val Thr Pro Pro Gly Leu Ala Arg Glu Asp Trp Lys Ile Ile Arg 610
615 620 Ala Leu Ser Glu
Ile Ala Gly Ile Thr Leu Pro Tyr Asp Thr Leu Asp 625 630
635 640 Gln Val Arg Asn Arg Leu Glu Glu Val
Ser Pro Asn Leu Val Arg Tyr 645 650
655 Asp Asp Ile Glu Glu Thr Asn Tyr Phe Gln Gln Ala Ser Glu
Leu Ala 660 665 670
Lys Leu Val Asn Gln Glu Val Leu Ala Asp Pro Leu Val Pro Pro Gln
675 680 685 Leu Thr Ile Lys
Asp Phe Tyr Met Thr Asp Ser Ile Ser Arg Ala Ser 690
695 700 Gln Thr Met Ala Lys Cys Val Lys
Ala Val Thr Glu Gly Ala Gln Ala 705 710
715 720 Val Glu Glu Pro Ser Ile Cys 725
16212PRTMus musculus 16Met Tyr Arg Leu Ser Ser Ser Met Leu Pro Arg
Ala Leu Ala Gln Ala 1 5 10
15 Met Arg Thr Gly His Leu Asn Gly Gln Ser Leu His Ser Ser Ala Val
20 25 30 Ala Ala
Thr Tyr Lys Tyr Val Asn Lys Lys Glu Gln Glu Ser Glu Val 35
40 45 Asp Met Lys Ser Ala Thr Asp
Asn Ala Ala Arg Ile Leu Met Trp Thr 50 55
60 Glu Leu Ile Arg Gly Leu Gly Met Thr Leu Ser Tyr
Leu Phe Arg Glu 65 70 75
80 Pro Ala Thr Ile Asn Tyr Pro Phe Glu Lys Gly Pro Leu Ser Pro Arg
85 90 95 Phe Arg Gly
Glu His Ala Leu Arg Arg Tyr Pro Ser Gly Glu Glu Arg 100
105 110 Cys Ile Ala Cys Lys Leu Cys Glu
Ala Ile Cys Pro Ala Gln Ala Ile 115 120
125 Thr Ile Glu Ala Glu Pro Arg Ala Asp Gly Ser Arg Arg
Thr Thr Arg 130 135 140
Tyr Asp Ile Asp Met Thr Lys Cys Ile Tyr Cys Gly Phe Cys Gln Glu 145
150 155 160 Ala Cys Pro Val
Asp Ala Ile Val Glu Gly Pro Asn Phe Glu Phe Ser 165
170 175 Thr Glu Thr His Glu Glu Leu Leu Tyr
Asn Lys Glu Lys Leu Leu Asn 180 185
190 Asn Gly Asp Lys Trp Glu Ala Glu Ile Ala Ala Asn Ile Gln
Ala Asp 195 200 205
Tyr Leu Tyr Arg 210 17480PRTMus musculus 17Met Ala Ala Ser
Ala Val Cys Arg Ala Ala Cys Ser Gly Thr Gln Val 1 5
10 15 Leu Leu Arg Thr Arg Arg Ser Pro Ala
Leu Leu Arg Leu Pro Ala Leu 20 25
30 Arg Gly Thr Ala Thr Phe Ala Gln Ala Leu Gln Ser Val Pro
Glu Thr 35 40 45
Gln Val Ser Ile Leu Asp Asn Gly Leu Arg Val Ala Ser Glu Gln Ser 50
55 60 Ser His Ala Thr Cys
Thr Val Gly Val Trp Ile Asp Ala Gly Ser Arg 65 70
75 80 Tyr Glu Thr Glu Lys Asn Asn Gly Ala Gly
Tyr Phe Leu Glu His Leu 85 90
95 Ala Phe Lys Gly Thr Lys Asn Arg Pro Gly Asn Ala Leu Glu Lys
Glu 100 105 110 Val
Glu Ser Ile Gly Ala His Leu Asn Ala Tyr Ser Thr Arg Glu His 115
120 125 Thr Ala Tyr Leu Ile Lys
Ala Leu Ser Lys Asp Leu Pro Lys Val Val 130 135
140 Glu Leu Leu Ala Asp Ile Val Gln Asn Ser Ser
Leu Glu Asp Ser Gln 145 150 155
160 Ile Glu Lys Glu Arg Asp Val Ile Leu Arg Glu Met Gln Glu Asn Asp
165 170 175 Ala Ser
Met Gln Asn Val Val Phe Asp Tyr Leu His Ala Thr Ala Phe 180
185 190 Gln Gly Thr Pro Leu Ala Gln
Ala Val Glu Gly Pro Ser Glu Asn Val 195 200
205 Arg Arg Leu Ser Arg Thr Asp Leu Thr Asp Tyr Leu
Asn Arg Asn Tyr 210 215 220
Lys Ala Pro Arg Met Val Leu Ala Ala Ala Gly Gly Val Glu His Gln 225
230 235 240 Gln Leu Leu
Asp Leu Ala Gln Lys His Leu Ser Ser Val Ser Arg Val 245
250 255 Tyr Glu Glu Asp Ala Val Pro Gly
Leu Thr Pro Cys Arg Phe Thr Gly 260 265
270 Ser Glu Ile Arg His Arg Asp Asp Ala Leu Pro Leu Ala
His Val Ala 275 280 285
Ile Ala Val Glu Gly Pro Gly Trp Ala Asn Pro Asp Asn Val Thr Leu 290
295 300 Gln Val Ala Asn
Ala Ile Ile Gly His Tyr Asp Cys Thr Cys Gly Gly 305 310
315 320 Gly Val His Leu Ser Ser Pro Leu Ala
Ser Val Ala Val Ala Asn Lys 325 330
335 Leu Cys Gln Ser Phe Gln Thr Phe Asn Ile Ser Tyr Ser Asp
Thr Gly 340 345 350
Leu Leu Gly Ala His Phe Val Cys Asp Ala Met Ser Ile Asp Asp Met
355 360 365 Val Phe Phe Leu
Gln Gly Gln Trp Met Arg Leu Cys Thr Ser Ala Thr 370
375 380 Glu Ser Glu Val Thr Arg Gly Lys
Asn Ile Leu Arg Asn Ala Leu Val 385 390
395 400 Ser His Leu Asp Gly Thr Thr Pro Val Cys Glu Asp
Ile Gly Arg Ser 405 410
415 Leu Leu Thr Tyr Gly Arg Arg Ile Pro Leu Ala Glu Trp Glu Ser Arg
420 425 430 Ile Gln Glu
Val Asp Ala Gln Met Leu Arg Asp Ile Cys Ser Lys Tyr 435
440 445 Phe Tyr Asp Gln Cys Pro Ala Val
Ala Gly Tyr Gly Pro Ile Glu Gln 450 455
460 Leu Pro Asp Tyr Asn Arg Ile Arg Ser Gly Met Phe Trp
Leu Arg Phe 465 470 475
480 18161PRTMus musculus 18Met Ala Gly Arg Lys Leu Ala Leu Lys Thr Ile
Asp Trp Val Ser Phe 1 5 10
15 Val Glu Val Met Pro Gln Asn Gln Lys Ala Ile Gly Asn Ala Leu Lys
20 25 30 Ser Trp
Asn Glu Thr Phe His Ala Arg Leu Ala Ser Leu Ser Glu Lys 35
40 45 Pro Pro Ala Ile Asp Trp Ala
Tyr Tyr Arg Ala Asn Val Ala Lys Pro 50 55
60 Gly Leu Val Asp Asp Phe Glu Lys Lys Tyr Asn Ala
Leu Lys Ile Pro 65 70 75
80 Val Pro Glu Asp Lys Tyr Thr Ala Leu Val Asp Gln Glu Glu Lys Glu
85 90 95 Asp Val Lys
Ser Cys Ala Glu Phe Val Ser Gly Ser Gln Leu Arg Ile 100
105 110 Gln Glu Tyr Glu Lys Gln Leu Glu
Lys Met Arg Asn Ile Ile Pro Phe 115 120
125 Asp Gln Met Thr Ile Asp Asp Leu Asn Glu Ile Phe Pro
Glu Thr Lys 130 135 140
Leu Asp Lys Lys Lys Tyr Pro Tyr Trp Pro His Gln Pro Ile Glu Asn 145
150 155 160 Leu 19381PRTMus
musculus 19Met Pro Phe Ser Asn Ser His Asn Thr Gln Lys Leu Arg Phe Pro
Ala 1 5 10 15 Glu
Asp Glu Phe Pro Asp Leu Ser Ser His Asn Asn His Met Ala Lys
20 25 30 Val Leu Thr Pro Glu
Leu Tyr Ala Glu Leu Arg Ala Lys Cys Thr Pro 35
40 45 Ser Gly Phe Thr Leu Asp Asp Ala Ile
Gln Thr Gly Val Asp Asn Pro 50 55
60 Gly His Pro Tyr Ile Met Thr Val Gly Ala Val Ala Gly
Asp Glu Glu 65 70 75
80 Ser Tyr Asp Val Phe Lys Asp Leu Phe Asp Pro Ile Ile Glu Glu Arg
85 90 95 His Gly Gly Tyr
Gln Pro Ser Asp Glu His Lys Thr Asp Leu Asn Pro 100
105 110 Asp Asn Leu Gln Gly Gly Asp Asp Leu
Asp Pro Asn Tyr Val Leu Ser 115 120
125 Ser Arg Val Arg Thr Gly Arg Ser Ile Arg Gly Phe Cys Leu
Pro Pro 130 135 140
His Cys Ser Arg Gly Glu Arg Arg Ala Ile Glu Lys Leu Ala Val Glu 145
150 155 160 Ala Leu Ser Ser Leu
Asp Gly Asp Leu Ser Gly Arg Tyr Tyr Ala Leu 165
170 175 Lys Ser Met Thr Glu Ala Glu Gln Gln Gln
Leu Ile Asp Asp His Phe 180 185
190 Leu Phe Asp Lys Pro Val Ser Pro Leu Leu Leu Ala Ser Gly Met
Ala 195 200 205 Arg
Asp Trp Pro Asp Ala Arg Gly Ile Trp His Asn Asp Asn Lys Thr 210
215 220 Phe Leu Val Trp Ile Asn
Glu Glu Asp His Leu Arg Val Ile Ser Met 225 230
235 240 Gln Lys Gly Gly Asn Met Lys Glu Val Phe Thr
Arg Phe Cys Thr Gly 245 250
255 Leu Thr Gln Ile Glu Thr Leu Phe Lys Ser Lys Asn Tyr Glu Phe Met
260 265 270 Trp Asn
Pro His Leu Gly Tyr Ile Leu Thr Cys Pro Ser Asn Leu Gly 275
280 285 Thr Gly Leu Arg Ala Gly Val
His Ile Lys Leu Pro His Leu Gly Lys 290 295
300 His Glu Lys Phe Ser Glu Val Leu Lys Arg Leu Arg
Leu Gln Lys Arg 305 310 315
320 Gly Thr Gly Gly Val Asp Thr Ala Ala Val Gly Gly Val Phe Asp Val
325 330 335 Ser Asn Ala
Asp Arg Leu Gly Phe Ser Glu Val Glu Leu Val Gln Met 340
345 350 Val Val Asp Gly Val Lys Leu Leu
Ile Glu Met Glu Gln Arg Leu Glu 355 360
365 Gln Gly Gln Ala Ile Asp Asp Leu Met Pro Ala Gln Lys
370 375 380 20646PRTMus musculus
20Met Ser Lys Gly Pro Ala Val Gly Ile Asp Leu Gly Thr Thr Tyr Ser 1
5 10 15 Cys Val Gly Val
Phe Gln His Gly Lys Val Glu Ile Ile Ala Asn Asp 20
25 30 Gln Gly Asn Arg Thr Thr Pro Ser Tyr
Val Ala Phe Thr Asp Thr Glu 35 40
45 Arg Leu Ile Gly Asp Ala Ala Lys Asn Gln Val Ala Met Asn
Pro Thr 50 55 60
Asn Thr Val Phe Asp Ala Lys Arg Leu Ile Gly Arg Arg Phe Asp Asp 65
70 75 80 Ala Val Val Gln Ser
Asp Met Lys His Trp Pro Phe Met Val Val Asn 85
90 95 Asp Ala Gly Arg Pro Lys Val Gln Val Glu
Tyr Lys Gly Glu Thr Lys 100 105
110 Ser Phe Tyr Pro Glu Glu Val Ser Ser Met Val Leu Thr Lys Met
Lys 115 120 125 Glu
Ile Ala Glu Ala Tyr Leu Gly Lys Thr Val Thr Asn Ala Val Val 130
135 140 Thr Val Pro Ala Tyr Phe
Asn Asp Ser Gln Arg Gln Ala Thr Lys Asp 145 150
155 160 Ala Gly Thr Ile Ala Gly Leu Asn Val Leu Arg
Ile Ile Asn Glu Pro 165 170
175 Thr Ala Ala Ala Ile Ala Tyr Gly Leu Asp Lys Lys Val Gly Ala Glu
180 185 190 Arg Asn
Val Leu Ile Phe Asp Leu Gly Gly Gly Thr Phe Asp Val Ser 195
200 205 Ile Leu Thr Ile Glu Asp Gly
Ile Phe Glu Val Lys Ser Thr Ala Gly 210 215
220 Asp Thr His Leu Gly Gly Glu Asp Phe Asp Asn Arg
Met Val Asn His 225 230 235
240 Phe Ile Ala Glu Phe Lys Arg Lys His Lys Lys Asp Ile Ser Glu Asn
245 250 255 Lys Arg Ala
Val Arg Arg Leu Arg Thr Ala Cys Glu Arg Ala Lys Arg 260
265 270 Thr Leu Ser Ser Ser Thr Gln Ala
Ser Ile Glu Ile Asp Ser Leu Tyr 275 280
285 Glu Gly Ile Asp Phe Tyr Thr Ser Ile Thr Arg Ala Arg
Phe Glu Glu 290 295 300
Leu Asn Ala Asp Leu Phe Arg Gly Thr Leu Asp Pro Val Glu Lys Ala 305
310 315 320 Leu Arg Asp Ala
Lys Leu Asp Lys Ser Gln Ile His Asp Ile Val Leu 325
330 335 Val Gly Gly Ser Thr Arg Ile Pro Lys
Ile Gln Lys Leu Leu Gln Asp 340 345
350 Phe Phe Asn Gly Lys Glu Leu Asn Lys Ser Ile Asn Pro Asp
Glu Ala 355 360 365
Val Ala Tyr Gly Ala Ala Val Gln Ala Ala Ile Leu Ser Gly Asp Lys 370
375 380 Ser Glu Asn Val Gln
Asp Leu Leu Leu Leu Asp Val Thr Pro Leu Ser 385 390
395 400 Leu Gly Ile Glu Thr Ala Gly Gly Val Met
Thr Val Leu Ile Lys Arg 405 410
415 Asn Thr Thr Ile Pro Thr Lys Gln Thr Gln Thr Phe Thr Thr Tyr
Ser 420 425 430 Asp
Asn Gln Pro Gly Val Leu Ile Gln Val Tyr Glu Gly Glu Arg Ala 435
440 445 Met Thr Lys Asp Asn Asn
Leu Leu Gly Lys Phe Glu Leu Thr Gly Ile 450 455
460 Pro Pro Ala Pro Arg Gly Val Pro Gln Ile Glu
Val Thr Phe Asp Ile 465 470 475
480 Asp Ala Asn Gly Ile Leu Asn Val Ser Ala Val Asp Lys Ser Thr Gly
485 490 495 Lys Glu
Asn Lys Ile Thr Ile Thr Asn Asp Lys Gly Arg Leu Ser Lys 500
505 510 Glu Asp Ile Glu Arg Met Val
Gln Glu Ala Glu Lys Tyr Lys Ala Glu 515 520
525 Asp Glu Lys Gln Arg Asp Lys Val Ser Ser Lys Asn
Ser Leu Glu Ser 530 535 540
Tyr Ala Phe Asn Met Lys Ala Thr Val Glu Asp Glu Lys Leu Gln Gly 545
550 555 560 Lys Ile Asn
Asp Glu Asp Lys Gln Lys Ile Leu Asp Lys Cys Asn Glu 565
570 575 Ile Ile Ser Trp Leu Asp Lys Asn
Gln Thr Ala Glu Glu Glu Glu Phe 580 585
590 Glu His Gln Gln Lys Glu Leu Glu Lys Val Cys Asn Pro
Ile Ile Thr 595 600 605
Lys Leu Tyr Gln Ser Ala Gly Gly Met Pro Gly Gly Met Pro Gly Gly 610
615 620 Phe Pro Gly Gly
Gly Ala Pro Pro Ser Gly Gly Ala Ser Ser Gly Pro 625 630
635 640 Thr Ile Glu Glu Val Asp
645 21679PRTMus musculus 21Met Ile Ser Ala Ser Arg Ala Ala Ala
Ala Arg Leu Val Gly Thr Ala 1 5 10
15 Ala Ser Arg Ser Pro Ala Ala Ala Arg Pro Gln Asp Gly Trp
Asn Gly 20 25 30
Leu Ser His Glu Ala Phe Arg Phe Val Ser Arg Arg Asp Tyr Ala Ser
35 40 45 Glu Ala Ile Lys
Gly Ala Val Val Gly Ile Asp Leu Gly Thr Thr Asn 50
55 60 Ser Cys Val Ala Val Met Glu Gly
Lys Gln Ala Lys Val Leu Glu Asn 65 70
75 80 Ala Glu Gly Ala Arg Thr Thr Pro Ser Val Val Ala
Phe Thr Ala Asp 85 90
95 Gly Glu Arg Leu Val Gly Met Pro Ala Lys Arg Gln Ala Val Thr Asn
100 105 110 Pro Asn Asn
Thr Phe Tyr Ala Thr Lys Arg Leu Ile Gly Arg Arg Tyr 115
120 125 Asp Asp Pro Glu Val Gln Lys Asp
Thr Lys Asn Val Pro Phe Lys Ile 130 135
140 Val Arg Ala Ser Asn Gly Asp Ala Trp Val Glu Ala His
Gly Lys Leu 145 150 155
160 Tyr Ser Pro Ser Gln Ile Gly Ala Phe Val Leu Met Lys Met Lys Glu
165 170 175 Thr Ala Glu Asn
Tyr Leu Gly His Thr Ala Lys Asn Ala Val Ile Thr 180
185 190 Val Pro Ala Tyr Phe Asn Asp Ser Gln
Arg Gln Ala Thr Lys Asp Ala 195 200
205 Gly Gln Ile Ser Gly Leu Asn Val Leu Arg Val Ile Asn Glu
Pro Thr 210 215 220
Ala Ala Ala Leu Ala Tyr Gly Leu Asp Lys Ser Glu Asp Lys Val Ile 225
230 235 240 Ala Val Tyr Asp Leu
Gly Gly Gly Thr Phe Asp Ile Ser Ile Leu Glu 245
250 255 Ile Gln Lys Gly Val Phe Glu Val Lys Ser
Thr Asn Gly Asp Thr Phe 260 265
270 Leu Gly Gly Glu Asp Phe Asp Gln Ala Leu Leu Arg His Ile Val
Lys 275 280 285 Glu
Phe Lys Arg Glu Thr Gly Val Asp Leu Thr Lys Asp Asn Met Ala 290
295 300 Leu Gln Arg Val Arg Glu
Ala Ala Glu Lys Ala Lys Cys Glu Leu Ser 305 310
315 320 Ser Ser Val Gln Thr Asp Ile Asn Leu Pro Tyr
Leu Thr Met Asp Ala 325 330
335 Ser Gly Pro Lys His Leu Asn Met Lys Leu Thr Arg Ala Gln Phe Glu
340 345 350 Gly Ile
Val Thr Asp Leu Ile Lys Arg Thr Ile Ala Pro Cys Gln Lys 355
360 365 Ala Met Gln Asp Ala Glu Val
Ser Lys Ser Asp Ile Gly Glu Val Ile 370 375
380 Leu Val Gly Gly Met Thr Arg Met Pro Lys Val Gln
Gln Thr Val Gln 385 390 395
400 Asp Leu Phe Gly Arg Ala Pro Ser Lys Ala Val Asn Pro Asp Glu Ala
405 410 415 Val Ala Ile
Gly Ala Ala Ile Gln Gly Gly Val Leu Ala Gly Asp Val 420
425 430 Thr Asp Val Leu Leu Leu Asp Val
Thr Pro Leu Ser Leu Gly Ile Glu 435 440
445 Thr Leu Gly Gly Val Phe Thr Lys Leu Ile Asn Arg Asn
Thr Thr Ile 450 455 460
Pro Thr Lys Lys Ser Gln Val Phe Ser Thr Ala Ala Asp Gly Gln Thr 465
470 475 480 Gln Val Glu Ile
Lys Val Cys Gln Gly Glu Arg Glu Met Ala Gly Asp 485
490 495 Asn Lys Leu Leu Gly Gln Phe Thr Leu
Ile Gly Ile Pro Pro Ala Pro 500 505
510 Arg Gly Val Pro Gln Ile Glu Val Thr Phe Asp Ile Asp Ala
Asn Gly 515 520 525
Ile Val His Val Ser Ala Lys Asp Lys Gly Thr Gly Arg Glu Gln Gln 530
535 540 Ile Val Ile Gln Ser
Ser Gly Gly Leu Ser Lys Asp Asp Ile Glu Asn 545 550
555 560 Met Val Lys Asn Ala Glu Lys Tyr Ala Glu
Glu Asp Arg Arg Lys Lys 565 570
575 Glu Arg Val Glu Ala Val Asn Met Ala Glu Gly Ile Ile His Asp
Thr 580 585 590 Glu
Thr Lys Met Glu Glu Phe Lys Asp Gln Leu Pro Ala Asp Glu Cys 595
600 605 Asn Lys Leu Lys Glu Glu
Ile Ser Lys Met Arg Ala Leu Leu Ala Gly 610 615
620 Lys Asp Ser Glu Thr Gly Glu Asn Ile Arg Gln
Ala Ala Ser Ser Leu 625 630 635
640 Gln Gln Ala Ser Leu Lys Leu Phe Glu Met Ala Tyr Lys Lys Met Ala
645 650 655 Ser Glu
Arg Glu Gly Ser Gly Ser Ser Gly Thr Gly Glu Gln Lys Glu 660
665 670 Asp Gln Lys Glu Glu Lys Gln
675 22679PRTMus musculus 22Met Ile Ser Ala Ser
Arg Ala Ala Ala Ala Arg Leu Val Gly Thr Ala 1 5
10 15 Ala Ser Arg Ser Pro Ala Ala Ala Arg Pro
Gln Asp Gly Trp Asn Gly 20 25
30 Leu Ser His Glu Ala Phe Arg Phe Val Ser Arg Arg Asp Tyr Ala
Ser 35 40 45 Glu
Ala Ile Lys Gly Ala Val Val Gly Ile Asp Leu Gly Thr Thr Asn 50
55 60 Ser Cys Val Ala Val Met
Glu Gly Lys Gln Ala Lys Val Leu Glu Asn 65 70
75 80 Ala Glu Gly Ala Arg Thr Thr Pro Ser Val Val
Ala Phe Thr Ala Asp 85 90
95 Gly Glu Arg Leu Val Gly Met Pro Ala Lys Arg Gln Ala Val Thr Asn
100 105 110 Pro Asn
Asn Thr Phe Tyr Ala Thr Lys Arg Ile Ile Gly Arg Arg Tyr 115
120 125 Asp Asp Pro Glu Val Gln Lys
Asp Thr Lys Asn Val Pro Phe Lys Ile 130 135
140 Val Arg Ala Ser Asn Gly Asp Ala Trp Val Glu Ala
His Gly Lys Leu 145 150 155
160 Tyr Ser Pro Ser Gln Ile Gly Ala Phe Val Leu Met Lys Met Lys Glu
165 170 175 Thr Ala Glu
Asn Tyr Leu Gly His Thr Ala Lys Asn Ala Val Ile Thr 180
185 190 Val Pro Ala Tyr Phe Asn Asp Ser
Gln Arg Asp Ala Thr Lys Asp Ala 195 200
205 Gly Gln Ile Ser Gly Leu Asn Val Leu Arg Val Ile Asn
Glu Pro Thr 210 215 220
Ala Ala Ala Leu Ala Tyr Gly Leu Asp Lys Ser Glu Asp Lys Val Ile 225
230 235 240 Ala Val Tyr Asp
Leu Gly Gly Gly Thr Phe Asp Ile Ser Ile Leu Glu 245
250 255 Ile Gln Lys Gly Val Phe Glu Val Lys
Ser Thr Asn Gly Asp Thr Phe 260 265
270 Leu Gly Gly Glu Asp Phe Asp Gln Ala Leu Leu Arg His Ile
Val Lys 275 280 285
Glu Phe Lys Arg Glu Thr Gly Val Asp Leu Thr Lys Asp Asn Met Ala 290
295 300 Leu Gln Arg Val Arg
Glu Ala Ala Glu Lys Ala Lys Cys Glu Leu Ser 305 310
315 320 Ser Ser Val Gln Thr Asp Ile Asn Leu Pro
Tyr Leu Thr Met Asp Ala 325 330
335 Ser Gly Pro Lys His Leu Asn Met Lys Leu Thr Arg Ala Gln Phe
Glu 340 345 350 Gly
Ile Val Thr Asp Leu Ile Lys Arg Thr Ile Ala Pro Cys Gln Lys 355
360 365 Ala Met Gln Asp Ala Glu
Val Ser Lys Ser Asp Ile Gly Glu Val Ile 370 375
380 Leu Val Gly Gly Met Thr Arg Met Pro Lys Val
Gln Gln Thr Val Gln 385 390 395
400 Asp Leu Phe Gly Arg Ala Pro Ser Lys Ala Val Asn Pro Asp Glu Ala
405 410 415 Val Ala
Ile Gly Ala Ala Ile Gln Gly Gly Val Leu Ala Gly Asp Val 420
425 430 Thr Asp Val Leu Leu Leu Asp
Val Thr Pro Leu Ser Leu Gly Ile Glu 435 440
445 Thr Leu Gly Gly Val Phe Thr Lys Leu Ile Asn Arg
Asn Thr Thr Ile 450 455 460
Pro Thr Lys Lys Ser Gln Val Phe Ser Thr Ala Ala Asp Gly Gln Thr 465
470 475 480 Gln Val Glu
Ile Lys Val Cys Gln Gly Glu Arg Glu Met Ala Gly Asp 485
490 495 Asn Lys Leu Leu Gly Gln Phe Thr
Leu Ile Gly Ile Pro Pro Ala Pro 500 505
510 Arg Gly Val Pro Gln Ile Glu Val Thr Phe Asp Ile Asp
Ala Asn Gly 515 520 525
Ile Val His Val Ser Ala Lys Asp Lys Gly Thr Gly Arg Glu Gln Gln 530
535 540 Ile Val Ile Gln
Ser Ser Gly Gly Leu Ser Lys Asp Asp Ile Glu Asn 545 550
555 560 Met Val Lys Asn Ala Glu Lys Tyr Ala
Glu Glu Asp Arg Arg Lys Lys 565 570
575 Glu Arg Val Glu Ala Val Asn Met Ala Glu Gly Ile Ile His
Asp Thr 580 585 590
Glu Thr Lys Met Glu Glu Phe Lys Asp Gln Leu Pro Ala Asp Glu Cys
595 600 605 Asn Lys Leu Lys
Glu Glu Ile Ser Lys Met Arg Ala Leu Leu Ala Gly 610
615 620 Lys Asp Ser Glu Thr Gly Glu Asn
Ile Arg Gln Ala Ala Ser Ser Leu 625 630
635 640 Gln Gln Ala Ser Leu Lys Leu Phe Glu Met Ala Tyr
Lys Lys Met Ala 645 650
655 Ser Glu Arg Glu Gly Ser Gly Ser Ser Gly Thr Gly Glu Gln Lys Glu
660 665 670 Asp Gln Lys
Glu Glu Lys Gln 675 23505PRTMus musculus 23Met
Arg Phe Ser Cys Leu Ala Leu Leu Pro Gly Val Ala Leu Leu Leu 1
5 10 15 Ala Ser Ala Arg Leu Ala
Ala Ala Ser Asp Val Leu Glu Leu Thr Asp 20
25 30 Glu Asn Phe Glu Ser Arg Val Ser Asp Thr
Gly Ser Ala Gly Leu Met 35 40
45 Leu Val Glu Phe Phe Ala Pro Trp Cys Gly His Cys Lys Arg
Leu Ala 50 55 60
Pro Glu Tyr Glu Ala Ala Ala Thr Arg Leu Lys Gly Ile Val Pro Leu 65
70 75 80 Ala Lys Val Asp Cys
Thr Ala Asn Thr Asn Thr Cys Asn Lys Tyr Gly 85
90 95 Val Ser Gly Tyr Pro Thr Leu Lys Ile Phe
Arg Asp Gly Glu Glu Ala 100 105
110 Gly Ala Tyr Asp Gly Pro Arg Thr Ala Asp Gly Ile Val Ser His
Leu 115 120 125 Lys
Lys Gln Ala Gly Pro Ala Ser Val Pro Leu Arg Thr Glu Glu Glu 130
135 140 Phe Lys Lys Phe Ile Ser
Asp Lys Asp Ala Ser Val Val Gly Phe Phe 145 150
155 160 Arg Asp Leu Phe Ser Asp Gly His Ser Glu Phe
Leu Lys Ala Ala Ser 165 170
175 Asn Leu Arg Asp Asn Tyr Arg Phe Ala His Thr Asn Ile Glu Ser Leu
180 185 190 Val Lys
Glu Tyr Asp Asp Asn Gly Glu Gly Ile Thr Ile Phe Arg Pro 195
200 205 Leu His Leu Ala Asn Lys Phe
Glu Asp Lys Thr Val Ala Tyr Thr Glu 210 215
220 Lys Lys Met Thr Ser Gly Lys Ile Lys Lys Phe Ile
Gln Asp Ser Ile 225 230 235
240 Phe Gly Leu Cys Pro His Met Thr Glu Asp Asn Lys Asp Leu Ile Gln
245 250 255 Gly Lys Asp
Leu Leu Thr Ala Tyr Tyr Asp Val Asp Tyr Glu Lys Asn 260
265 270 Ala Lys Gly Ser Asn Tyr Trp Arg
Asn Arg Val Met Met Val Ala Lys 275 280
285 Lys Phe Leu Asp Ala Gly His Lys Leu Asn Phe Ala Val
Ala Ser Arg 290 295 300
Lys Thr Phe Ser His Glu Leu Ser Asp Phe Gly Leu Glu Ser Thr Thr 305
310 315 320 Gly Glu Val Pro
Val Val Ala Ile Arg Thr Ala Lys Gly Glu Lys Phe 325
330 335 Val Met Gln Glu Glu Phe Ser Arg Asp
Gly Lys Ala Leu Glu Gln Phe 340 345
350 Leu Gln Glu Tyr Phe Asp Gly Asn Leu Lys Arg Tyr Leu Lys
Ser Glu 355 360 365
Pro Ile Pro Glu Ser Asn Glu Gly Pro Val Lys Val Val Val Ala Glu 370
375 380 Asn Phe Asp Asp Ile
Val Asn Glu Glu Asp Lys Asp Val Leu Ile Glu 385 390
395 400 Phe Tyr Ala Pro Trp Cys Gly His Cys Lys
Asn Leu Glu Pro Lys Tyr 405 410
415 Lys Glu Leu Gly Glu Lys Leu Ser Lys Asp Pro Asn Ile Val Ile
Ala 420 425 430 Lys
Met Asp Ala Thr Ala Asn Asp Val Pro Ser Pro Tyr Glu Val Lys 435
440 445 Gly Phe Pro Thr Ile Tyr
Phe Ser Pro Ala Asn Lys Lys Leu Thr Pro 450 455
460 Lys Lys Tyr Glu Gly Gly Arg Glu Leu Asn Asp
Phe Ile Ser Tyr Leu 465 470 475
480 Gln Arg Glu Ala Thr Asn Pro Pro Ile Ile Gln Glu Glu Lys Pro Lys
485 490 495 Lys Lys
Lys Lys Ala Gln Glu Asp Leu 500 505
24617PRTMus musculus 24Met Asp Phe Ser Lys Leu Pro Lys Ile Arg Asp Glu
Asp Lys Glu Ser 1 5 10
15 Thr Phe Gly Tyr Val His Gly Val Ser Gly Pro Val Val Thr Ala Cys
20 25 30 Asp Met Ala
Gly Ala Ala Met Tyr Glu Leu Val Arg Val Gly His Ser 35
40 45 Glu Leu Val Gly Glu Ile Ile Arg
Leu Glu Gly Asp Met Ala Thr Ile 50 55
60 Gln Val Tyr Glu Glu Thr Ser Gly Val Ser Val Gly Asp
Pro Val Leu 65 70 75
80 Arg Thr Gly Lys Pro Arg Ser Val Glu Leu Gly Pro Gly Ile Met Gly
85 90 95 Ala Ile Phe Asp
Gly Ile Gln Arg Pro Leu Ser Asp Ile Ser Ser Gln 100
105 110 Thr Gln Ser Ile Tyr Ile Pro Arg Gly
Val Asn Val Ser Ala Leu Ser 115 120
125 Arg Asp Ile Lys Trp Glu Phe Ile Pro Ser Lys Asn Leu Arg
Val Gly 130 135 140
Ser His Ile Thr Gly Gly Asp Ile Tyr Gly Ile Val Asn Glu Asn Ser 145
150 155 160 Leu Ile Lys His Lys
Ile Met Leu Pro Pro Arg Asn Arg Gly Ser Val 165
170 175 Thr Tyr Ile Ala Pro Pro Gly Asn Tyr Asp
Ala Ser Asn Val Val Leu 180 185
190 Glu Leu Glu Phe Glu Gly Val Lys Glu Lys Phe Ser Met Val Gln
Val 195 200 205 Trp
Pro Val Arg Gln Val Arg Pro Val Thr Glu Lys Leu Pro Ala Asn 210
215 220 His Pro Leu Leu Thr Gly
Gln Arg Val Leu Asp Ala Leu Phe Pro Cys 225 230
235 240 Val Gln Gly Gly Thr Thr Ala Ile Pro Gly Ala
Phe Gly Cys Gly Lys 245 250
255 Thr Val Ile Ser Gln Ser Leu Ser Lys Tyr Ser Asn Ser Asp Val Ile
260 265 270 Ile Tyr
Val Gly Cys Gly Glu Arg Gly Asn Glu Met Ser Glu Val Leu 275
280 285 Arg Asp Phe Pro Glu Leu Thr
Met Glu Val Asp Gly Lys Ala Glu Ser 290 295
300 Ile Met Lys Arg Thr Ala Leu Val Ala Asn Thr Ser
Asn Met Pro Val 305 310 315
320 Ala Ala Arg Glu Ala Ser Ile Tyr Thr Gly Ile Thr Leu Ser Glu Tyr
325 330 335 Phe Arg Asp
Met Gly Tyr His Val Ser Met Met Ala Asp Ser Thr Ser 340
345 350 Arg Trp Ala Glu Ala Leu Arg Glu
Ile Ser Gly Arg Leu Ala Glu Met 355 360
365 Pro Ala Asp Ser Gly Tyr Pro Ala Tyr Leu Gly Ala Arg
Leu Ala Ser 370 375 380
Phe Tyr Glu Arg Ala Gly Arg Val Lys Cys Leu Gly Asn Pro Glu Arg 385
390 395 400 Glu Gly Ser Val
Ser Ile Val Gly Ala Val Ser Pro Pro Gly Gly Asp 405
410 415 Phe Ser Asp Pro Val Thr Ser Ala Thr
Leu Gly Ile Val Gln Val Phe 420 425
430 Trp Gly Leu Asp Lys Lys Leu Ala Gln Arg Lys His Phe Pro
Ser Val 435 440 445
Asn Trp Leu Ile Ser Tyr Ser Lys Tyr Met Arg Ala Leu Asp Glu Tyr 450
455 460 Tyr Asp Lys His Phe
Thr Glu Phe Val Pro Leu Arg Thr Lys Ala Lys 465 470
475 480 Glu Ile Leu Gln Glu Glu Gly Asp Leu Ala
Glu Ile Val Gln Leu Val 485 490
495 Gly Lys Ala Ser Leu Ala Glu Thr Asp Lys Ile Thr Leu Glu Val
Ala 500 505 510 Lys
Leu Ile Lys Asp Asp Phe Leu Gln Gln Asn Gly Tyr Thr Pro Tyr 515
520 525 Asp Arg Phe Cys Pro Phe
Tyr Lys Thr Val Gly Met Leu Ser Asn Met 530 535
540 Ile Ser Phe Tyr Asp Met Ala Arg Arg Ala Val
Glu Thr Thr Ala Gln 545 550 555
560 Ser Asp Asn Lys Ile Thr Trp Ser Ile Ile Arg Glu His Met Gly Glu
565 570 575 Ile Leu
Tyr Lys Leu Ser Ser Met Lys Phe Lys Asp Pro Val Lys Asp 580
585 590 Gly Glu Ala Lys Ile Lys Ala
Asp Tyr Ala Gln Leu Leu Glu Asp Met 595 600
605 Gln Asn Ala Phe Arg Ser Leu Glu Asp 610
615 25418PRTMus musculus 25Met Glu Glu Ile Gly Ile
Leu Val Glu Lys Ile Gln Asp Glu Ile Pro 1 5
10 15 Ala Leu Ser Val Ser Arg Pro Gln Thr Gly Leu
Ser Phe Leu Gly Pro 20 25
30 Glu Pro Glu Asp Leu Glu Asp Leu Tyr Ser Arg Tyr Lys Lys Leu
Gln 35 40 45 Gln
Glu Leu Glu Phe Leu Glu Val Gln Glu Glu Tyr Ile Lys Asp Glu 50
55 60 Gln Lys Asn Leu Lys Lys
Glu Phe Leu His Ala Gln Glu Glu Val Lys 65 70
75 80 Arg Ile Gln Ser Ile Pro Leu Val Ile Gly Gln
Phe Leu Glu Ala Val 85 90
95 Asp Gln Asn Thr Ala Ile Val Gly Ser Thr Thr Gly Ser Asn Tyr Tyr
100 105 110 Val Arg
Ile Leu Ser Thr Ile Asp Arg Glu Leu Leu Lys Pro Asn Ala 115
120 125 Ser Val Ala Leu His Lys His
Ser Asn Ala Leu Val Asp Val Leu Pro 130 135
140 Pro Glu Ala Asp Ser Ser Ile Met Met Leu Thr Ser
Asp Gln Lys Pro 145 150 155
160 Asp Val Met His Ala Asp Ile Gly Gly Met Asp Ile Gln Lys Gln Glu
165 170 175 Val Arg Glu
Ala Val Glu Leu Pro Leu Thr His Phe Glu Leu Tyr Lys 180
185 190 Gln Ile Gly Ile Asp Pro Pro Arg
Gly Val Leu Met Tyr Gly Pro Pro 195 200
205 Gly Cys Gly Lys Thr Met Leu Ala Lys Ala Val Ala His
His Thr Thr 210 215 220
Ala Ala Phe Ile Arg Val Val Gly Ser Glu Phe Val Gln Lys Tyr Leu 225
230 235 240 Gly Glu Gly Pro
Arg Met Val Arg Asp Val Phe Arg Leu Ala Lys Glu 245
250 255 Asn Ala Pro Ala Ile Ile Phe Ile Asp
Glu Ile Asp Ala Ile Ala Thr 260 265
270 Lys Arg Phe Asp Ala Gln Thr Gly Ala Asp Arg Glu Val Gln
Arg Ile 275 280 285
Leu Leu Glu Leu Leu Asn Gln Met Asp Gly Phe Asp Gln Asn Val Asn 290
295 300 Val Lys Val Ile Met
Ala Thr Asn Arg Ala Asp Thr Leu Asp Pro Ala 305 310
315 320 Leu Leu Arg Pro Gly Arg Leu Asp Arg Lys
Ile Glu Phe Pro Leu Pro 325 330
335 Asp Arg Arg Gln Lys Arg Leu Ile Phe Ser Thr Ile Thr Ser Lys
Met 340 345 350 Asn
Leu Ser Glu Glu Val Asp Leu Glu Asp Tyr Val Ala Arg Pro Asp 355
360 365 Lys Ile Ser Gly Ala Asp
Ile Asn Ser Ile Cys Gln Glu Ser Gly Met 370 375
380 Leu Ala Val Arg Glu Asn Arg Tyr Ile Val Leu
Ala Lys Asp Phe Glu 385 390 395
400 Lys Ala Tyr Lys Thr Val Ile Lys Lys Asp Glu Gln Glu His Glu Phe
405 410 415 Tyr Lys
26234PRTMus musculus 26Met Ala Lys Arg Gly Tyr Ser Phe Ser Leu Thr Thr
Phe Ser Pro Ser 1 5 10
15 Gly Lys Leu Val Gln Ile Glu Tyr Ala Leu Ala Ala Val Ala Gly Gly
20 25 30 Ala Pro Ser
Val Gly Ile Lys Ala Ala Asn Gly Val Val Leu Ala Thr 35
40 45 Glu Lys Lys Gln Lys Ser Ile Leu
Tyr Asp Glu Arg Ser Val His Lys 50 55
60 Val Glu Pro Ile Thr Lys His Ile Gly Leu Val Tyr Ser
Gly Met Gly 65 70 75
80 Pro Asp Tyr Arg Val Leu Val His Arg Ala Arg Lys Leu Ala Gln Gln
85 90 95 Tyr Tyr Leu Val
Tyr Gln Glu Pro Ile Pro Thr Ala Gln Leu Val Gln 100
105 110 Arg Val Ala Ser Val Met Gln Glu Tyr
Thr Gln Ser Gly Gly Val Arg 115 120
125 Pro Phe Gly Val Ser Leu Leu Ile Cys Gly Trp Asn Glu Gly
Arg Pro 130 135 140
Tyr Leu Phe Gln Ser Asp Pro Ser Gly Ala Tyr Phe Ala Trp Lys Ala 145
150 155 160 Thr Ala Met Gly Lys
Asn Tyr Val Asn Gly Lys Thr Phe Leu Glu Lys 165
170 175 Arg Tyr Asn Glu Asp Leu Glu Leu Glu Asp
Ala Ile His Thr Ala Ile 180 185
190 Leu Thr Leu Lys Glu Ser Phe Glu Gly Gln Met Thr Glu Asp Asn
Ile 195 200 205 Glu
Val Gly Ile Cys Asn Glu Ala Gly Phe Arg Arg Leu Thr Pro Thr 210
215 220 Glu Val Arg Asp Tyr Leu
Ala Ala Ile Ala 225 230 27233PRTMus
musculus 27Gly Leu Cys Leu Gln Val Pro Ser Ala Lys Met Gln Leu Lys Pro
Met 1 5 10 15 Glu
Ile Asn Pro Glu Met Leu Asn Lys Val Leu Ala Lys Leu Gly Val
20 25 30 Ala Gly Gln Trp Arg
Phe Ala Asp Val Leu Gly Leu Glu Glu Glu Thr 35
40 45 Leu Gly Ser Val Pro Ser Pro Ala Cys
Ala Leu Leu Leu Leu Phe Pro 50 55
60 Leu Thr Ala Gln His Glu Asn Phe Arg Lys Lys Gln Ile
Glu Glu Leu 65 70 75
80 Lys Gly Gln Glu Val Ser Pro Lys Val Tyr Phe Met Lys Gln Thr Ile
85 90 95 Gly Asn Ser Cys
Gly Thr Ile Gly Leu Ile His Ala Val Ala Asn Asn 100
105 110 Gln Asp Lys Leu Glu Phe Glu Asp Gly
Ser Val Leu Lys Gln Phe Leu 115 120
125 Ser Glu Thr Glu Lys Leu Ser Pro Glu Asp Arg Ala Lys Cys
Phe Glu 130 135 140
Lys Asn Glu Ala Ile Gln Ala Ala His Asp Ser Val Ala Gln Glu Gly 145
150 155 160 Gln Cys Arg Val Asp
Asp Lys Val Asn Phe His Phe Ile Leu Phe Asn 165
170 175 Asn Val Asp Gly His Leu Tyr Glu Leu Asp
Gly Arg Met Pro Phe Pro 180 185
190 Val Asn His Gly Ala Ser Ser Glu Asp Ser Leu Leu Gln Asp Ala
Ala 195 200 205 Lys
Val Cys Arg Glu Phe Thr Glu Arg Glu Gln Gly Glu Val Arg Phe 210
215 220 Ser Ala Val Ala Leu Cys
Lys Ala Ala 225 230 28822PRTMus musculus
28Pro Leu Pro Ser Gly Arg His Ser Arg Arg Pro Gly Glu Ala Arg Ala 1
5 10 15 Met Ala Ser Gly
Ala Asp Ser Lys Gly Asp Asp Leu Ser Thr Ala Ile 20
25 30 Leu Lys Gln Lys Asn Arg Pro Asn Arg
Leu Ile Val Asp Glu Ala Ile 35 40
45 Asn Glu Asp Asn Ser Val Val Ser Leu Ser Gln Pro Lys Met
Asp Glu 50 55 60
Leu Gln Leu Phe Arg Gly Asp Thr Val Leu Leu Lys Gly Lys Lys Arg 65
70 75 80 Arg Glu Ala Val Cys
Ile Val Leu Ser Asp Asp Thr Cys Ser Asp Glu 85
90 95 Lys Ile Arg Met Asn Arg Val Val Arg Asn
Asn Leu Arg Val Arg Leu 100 105
110 Gly Asp Val Ile Ser Ile Gln Pro Cys Pro Asp Val Lys Tyr Gly
Lys 115 120 125 Arg
Ile His Val Leu Pro Ile Asp Asp Thr Val Glu Gly Ile Thr Gly 130
135 140 Asn Leu Phe Glu Val Tyr
Leu Lys Pro Tyr Phe Leu Glu Ala Tyr Arg 145 150
155 160 Pro Ile Arg Lys Gly Asp Ile Phe Leu Val Arg
Gly Gly Met Arg Ala 165 170
175 Val Glu Phe Lys Val Val Glu Thr Asp Pro Ser Pro Tyr Cys Ile Val
180 185 190 Ala Pro
Asp Thr Val Ile His Cys Glu Gly Glu Pro Ile Lys Arg Glu 195
200 205 Asp Glu Glu Glu Ser Leu Asn
Glu Val Gly Tyr Asp Asp Ile Gly Gly 210 215
220 Cys Arg Lys Gln Leu Ala Gln Ile Lys Glu Met Val
Glu Leu Pro Leu 225 230 235
240 Arg His Pro Ala Leu Phe Lys Ala Ile Gly Val Lys Pro Pro Arg Gly
245 250 255 Ile Leu Leu
Tyr Gly Pro Pro Gly Thr Gly Lys Thr Leu Ile Ala Arg 260
265 270 Ala Val Ala Asn Glu Thr Gly Ala
Phe Phe Phe Leu Ile Asn Gly Pro 275 280
285 Glu Ile Met Ser Lys Leu Ala Gly Glu Ser Glu Ser Asn
Leu Arg Lys 290 295 300
Ala Phe Glu Glu Ala Glu Lys Asn Ala Pro Ala Ile Ile Phe Ile Asp 305
310 315 320 Glu Leu Asp Ala
Ile Ala Pro Lys Arg Glu Lys Thr His Gly Glu Val 325
330 335 Glu Arg Arg Ile Val Ser Gln Leu Leu
Thr Leu Met Asp Gly Leu Lys 340 345
350 Gln Arg Ala His Val Ile Val Met Ala Ala Thr Asn Arg Pro
Asn Ser 355 360 365
Ile Asp Pro Ala Leu Arg Arg Phe Gly Arg Phe Asp Arg Glu Val Asp 370
375 380 Ile Gly Ile Pro Asp
Ala Thr Gly Arg Leu Glu Ile Leu Gln Ile His 385 390
395 400 Thr Lys Asn Met Lys Leu Ala Asp Asp Val
Asp Leu Glu Gln Val Ala 405 410
415 Asn Glu Thr His Gly His Val Gly Ala Asp Leu Ala Ala Leu Cys
Ser 420 425 430 Glu
Ala Ala Leu Gln Ala Ile Arg Lys Lys Met Asp Leu Ile Asp Leu 435
440 445 Glu Asp Glu Thr Ile Asp
Ala Glu Val Met Asn Ser Leu Ala Val Thr 450 455
460 Met Asp Asp Phe Arg Trp Ala Leu Ser Gln Ser
Asn Pro Ser Ala Leu 465 470 475
480 Arg Glu Thr Val Val Glu Val Pro Gln Val Thr Trp Glu Asp Ile Gly
485 490 495 Gly Leu
Glu Asp Val Lys Arg Glu Leu Gln Glu Leu Val Gln Tyr Pro 500
505 510 Val Glu His Pro Asp Lys Phe
Leu Lys Phe Gly Met Thr Pro Ser Lys 515 520
525 Gly Val Leu Phe Tyr Gly Pro Pro Gly Cys Gly Lys
Thr Leu Leu Ala 530 535 540
Lys Ala Ile Ala Asn Glu Cys Gln Ala Asn Phe Ile Ser Ile Lys Gly 545
550 555 560 Pro Glu Leu
Leu Thr Met Trp Phe Gly Glu Ser Glu Ala Asn Val Arg 565
570 575 Glu Ile Phe Asp Lys Ala Arg Gln
Ala Ala Pro Cys Val Leu Phe Phe 580 585
590 Asp Glu Leu Asp Ser Ile Ala Lys Ala Arg Gly Gly Asn
Ile Gly Asp 595 600 605
Gly Gly Gly Ala Ala Asp Arg Val Ile Asn Gln Ile Leu Thr Glu Met 610
615 620 Asp Gly Met Ser
Thr Lys Lys Asn Val Phe Ile Ile Gly Ala Thr Asn 625 630
635 640 Arg Pro Asp Ile Ile Asp Pro Ala Ile
Leu Arg Pro Gly Arg Leu Asp 645 650
655 Gln Leu Ile Tyr Ile Pro Leu Pro Asp Glu Lys Ser Arg Val
Ala Ile 660 665 670
Leu Lys Ala Asn Leu Arg Lys Ser Pro Val Ala Lys Asp Val Asp Leu
675 680 685 Glu Phe Leu Ala
Lys Met Thr Asn Gly Phe Ser Gly Ala Asp Leu Thr 690
695 700 Glu Ile Cys Gln Arg Ala Cys Lys
Leu Ala Ile Arg Glu Ser Ile Glu 705 710
715 720 Ser Glu Ile Arg Arg Glu Arg Glu Arg Gln Thr Asn
Pro Ser Ala Met 725 730
735 Glu Val Glu Glu Asp Asp Pro Val Pro Glu Ile Arg Arg Asp His Phe
740 745 750 Glu Glu Ala
Met Arg Phe Ala Arg Arg Ser Val Ser Asp Asn Asp Ile 755
760 765 Arg Lys Tyr Glu Met Phe Ala Gln
Thr Leu Gln Gln Ser Arg Gly Phe 770 775
780 Gly Ser Phe Arg Phe Pro Ser Gly Asn Gln Gly Gly Ala
Gly Pro Ser 785 790 795
800 Gln Gly Ser Gly Gly Gly Thr Gly Gly Ser Val Tyr Thr Glu Asp Asn
805 810 815 Asp Asp Asp Leu
Tyr Gly 820 29334PRTMus musculus 29Met Ala Ala Ser
Leu Gly Phe Arg Gly Ala Ala Ser Gly Leu Trp Tyr 1 5
10 15 Trp Ser Gly Arg Arg Arg Pro Val Gly
Ser Leu Ala Ala Val Cys Ser 20 25
30 Arg Ser Met Ala Ser Lys Thr Pro Val Gly Phe Ile Gly Leu
Gly Asn 35 40 45
Met Gly Asn Pro Met Ala Lys Asn Leu Met Lys His Gly Tyr Pro Leu 50
55 60 Ile Leu Tyr Asp Val
Phe Pro Asp Val Cys Lys Glu Phe Lys Glu Ala 65 70
75 80 Gly Glu Gln Val Ala Ser Ser Pro Ala Glu
Val Ala Glu Lys Ala Asp 85 90
95 Arg Ile Ile Thr Met Leu Pro Ser Ser Met Asn Ala Val Glu Val
Tyr 100 105 110 Ser
Gly Ala Asn Gly Ile Leu Lys Lys Val Lys Lys Gly Ser Leu Leu 115
120 125 Ile Asp Ser Ser Thr Met
Ile Leu Gln Phe Gln Lys Asn Gly Lys Arg 130 135
140 Ser Glu Lys Met Gly Ala Val Phe Met Asp Ala
Pro Val Ser Gly Gly 145 150 155
160 Val Gly Ala Ala Arg Ser Gly Asn Leu Thr Phe Met Val Gly Gly Val
165 170 175 Glu Asp
Glu Phe Ala Ala Ala Gln Glu Leu Leu Glu Cys Met Gly Ser 180
185 190 Asn Val Val Tyr Cys Gly Ala
Val Gly Thr Gly Gln Ser Ala Gln Ile 195 200
205 Cys Asn Asn Met Leu Leu Ala Ile Ser Met Ile Gly
Thr Ala Glu Ala 210 215 220
Met Asn Leu Gly Ile Arg Ser Gly Leu Asp Pro Lys Leu Leu Ala Lys 225
230 235 240 Ile Leu Asn
Met Ser Ser Gly Arg Cys Trp Ser Ser Asp Thr Tyr Asn 245
250 255 Pro Val Pro Gly Phe Met His Gly
Val Pro Ser Ser Asn Asn Tyr Gln 260 265
270 Gly Gly Phe Gly Thr Thr Leu Met Ala Lys Asp Leu Gly
Leu Ala Gln 275 280 285
Asp Ser Ala Thr Ser Thr Lys Thr Pro Ile Leu Leu Gly Ser Leu Ala 290
295 300 His Gln Ile Tyr
Arg Met Met Cys Ser Lys Gly Tyr Ser Lys Lys Asp 305 310
315 320 Phe Ser Ser Val Phe Gln Tyr Leu Arg
Glu Glu Glu Pro Phe 325 330
30291PRTMus musculus 30 Met Ala Thr Ala Thr Val Arg Pro Ala Ala Gln Arg
Leu Arg Leu Leu 1 5 10
15 Leu Ser Pro Leu Lys Ser Arg Ile Cys Val Pro Gln Ala Glu Pro Val
20 25 30 Ala Thr Phe
Gly Thr Ala Val Thr Ser Ala Lys Val Ala Val Asn Gly 35
40 45 Val His Leu His Tyr Gln Arg Val
Gly Glu Gly Glu His Ala Ile Leu 50 55
60 Leu Leu Pro Gly Met Leu Gly Ser Gly Lys Thr Asp Phe
Ala Pro Gln 65 70 75
80 Leu Gln Ser Leu Asn Lys Lys Arg Phe Thr Leu Val Ala Trp Asp Pro
85 90 95 Arg Gly Tyr Gly
Tyr Ser Arg Pro Pro Asp Arg Asp Phe Pro Arg Asp 100
105 110 Phe Phe Glu Arg Asp Ala Lys Asp Ala
Val Asp Leu Met Lys Ala Leu 115 120
125 Gln Phe Lys Gln Val Ser Leu Leu Gly Trp Ser Asp Gly Gly
Ile Thr 130 135 140
Ala Leu Ile Ala Ala Ala Lys Tyr Pro Ser Tyr Ile Arg Lys Met Val 145
150 155 160 Ile Trp Gly Ala Asn
Ala Tyr Val Thr Glu Glu Asp Ser Arg Ile Tyr 165
170 175 Gln Gly Ile Arg Asp Val Ser Lys Trp Ser
Glu Lys Ala Arg Lys Pro 180 185
190 Leu Glu Ala Leu Tyr Gly Tyr Asp Tyr Leu Ala Lys Thr Cys Glu
Asp 195 200 205 Trp
Val Asp Gly Ile Ser Gln Phe Lys Gln Leu Pro Glu Gly Asn Ile 210
215 220 Cys Arg His Leu Leu Pro
Leu Val Gln Cys Pro Thr Leu Ile Val His 225 230
235 240 Gly Glu Lys Asp Pro Leu Val Pro Arg Phe His
Ala Asp Phe Leu Leu 245 250
255 Gln His Val Lys Gly Ser Arg Leu His Leu Met Pro Glu Gly Lys His
260 265 270 Asn Leu
His Leu Arg Phe Ala Asp Glu Phe Asn Arg Leu Val Glu Asp 275
280 285 Phe Leu Gln 290
31259PRTMus musculus 31Met Ala Ala Arg Arg Ala Leu Lys Ala Val Leu Val
Asp Leu Asn Gly 1 5 10
15 Thr Leu His Ile Glu Asp Ala Ala Val Pro Gly Ala Gln Glu Ala Leu
20 25 30 Lys Arg Leu
Arg Ala Thr Ser Val Met Val Arg Phe Val Thr Asn Thr 35
40 45 Thr Lys Glu Thr Lys Lys Asp Leu
Leu Glu Arg Leu Lys Lys Leu Glu 50 55
60 Phe Glu Ile Ser Glu Asp Glu Ile Phe Thr Ser Leu Thr
Ala Ala Arg 65 70 75
80 Asn Leu Ile Glu Gln Lys Gln Val Arg Pro Met Leu Leu Val Asp Asp
85 90 95 Arg Ala Leu Pro
Glu Phe Thr Gly Val Gln Thr Gln Asp Pro Asn Ala 100
105 110 Val Val Ile Gly Leu Ala Pro Glu His
Phe His Tyr Gln Leu Leu Asn 115 120
125 Gln Ala Phe Arg Leu Leu Leu Asp Gly Ala Pro Leu Ile Ala
Ile His 130 135 140
Lys Ala Arg Tyr Tyr Lys Arg Lys Asp Gly Leu Ala Leu Gly Pro Gly 145
150 155 160 Pro Phe Val Thr Ala
Leu Glu Tyr Ala Thr Asp Thr Lys Ala Met Val 165
170 175 Val Gly Lys Pro Glu Lys Thr Phe Phe Leu
Glu Ala Leu Arg Asp Ala 180 185
190 Asp Cys Ala Pro Glu Glu Ala Val Met Ile Gly Asp Asp Cys Arg
Asp 195 200 205 Asp
Val Asp Gly Ala Gln Asn Ile Gly Met Leu Gly Ile Leu Val Lys 210
215 220 Thr Gly Lys Tyr Lys Ala
Ala Asp Glu Glu Lys Ile Asn Pro Pro Pro 225 230
235 240 Tyr Leu Thr Cys Glu Ser Phe Pro His Ala Val
Asp His Ile Leu Gln 245 250
255 His Leu Leu 32349PRTMus musculus 32Pro Arg Ala Val Phe Pro Ser
Ile Val Gly Arg Ser Arg His Gln Gly 1 5
10 15 Val Met Val Gly Met Gly Gln Lys Asp Ser Tyr
Val Gly Asp Glu Ala 20 25
30 Gln Ser Lys Arg Gly Ile Leu Thr Leu Lys Tyr Pro Ile Glu His
Gly 35 40 45 Ile
Val Thr Asn Trp Asp Asp Met Glu Lys Ile Trp His His Thr Phe 50
55 60 Tyr Asn Glu Leu Arg Val
Ala Pro Glu Glu His Pro Val Leu Leu Thr 65 70
75 80 Glu Ala Pro Leu Asn Pro Lys Ala Asn Arg Glu
Lys Met Thr Gln Ile 85 90
95 Met Phe Glu Thr Phe Asn Thr Pro Ala Met Tyr Val Ala Ile Gln Ala
100 105 110 Val Leu
Ser Leu Tyr Ala Ser Gly Arg Thr Thr Gly Ile Val Met Asp 115
120 125 Ser Gly Asp Gly Val Thr His
Thr Val Pro Ile Tyr Glu Gly Tyr Ala 130 135
140 Leu Pro His Ala Ile Leu Arg Leu Asp Leu Ala Gly
Arg Asp Leu Thr 145 150 155
160 Asp Tyr Leu Met Lys Ile Leu Thr Glu Arg Gly Tyr Ser Phe Thr Thr
165 170 175 Thr Ala Glu
Arg Glu Ile Val Arg Asp Ile Lys Glu Lys Leu Cys Tyr 180
185 190 Val Ala Leu Asp Phe Glu Gln Glu
Met Ala Thr Ala Ala Ser Ser Ser 195 200
205 Ser Leu Glu Lys Ser Tyr Glu Leu Pro Asp Gly Gln Val
Ile Thr Ile 210 215 220
Gly Asn Glu Arg Phe Arg Cys Pro Glu Ala Leu Phe Gln Pro Ser Phe 225
230 235 240 Leu Gly Met Glu
Ser Cys Gly Ile His Glu Thr Thr Phe Asn Ser Ile 245
250 255 Met Lys Cys Asp Val Asp Ile Arg Lys
Asp Leu Tyr Ala Asn Thr Val 260 265
270 Leu Ser Gly Gly Thr Thr Met Tyr Pro Gly Ile Ala Asp Arg
Met Gln 275 280 285
Lys Glu Ile Thr Ala Leu Ala Pro Ser Thr Met Lys Ile Lys Ile Ile 290
295 300 Ala Pro Pro Glu Arg
Lys Tyr Ser Val Trp Ile Gly Gly Ser Ile Leu 305 310
315 320 Ala Ser Leu Ser Thr Phe Gln Gln Met Trp
Ile Ser Lys Gln Glu Tyr 325 330
335 Asp Glu Ser Gly Pro Ser Ile Val His Arg Lys Cys Phe
340 345 33368PRTMus musculus 33Leu
Val Ile Asp Asn Gly Ser Gly Met Cys Lys Ala Gly Phe Ala Gly 1
5 10 15 Asp Asp Ala Pro Arg Ala
Val Phe Pro Ser Ile Val Gly Arg Pro Arg 20
25 30 His Gln Gly Val Met Val Gly Met Gly Gln
Lys Asp Ser Tyr Val Gly 35 40
45 Asp Glu Ala Gln Ser Lys Arg Gly Ile Leu Thr Leu Lys Tyr
Pro Ile 50 55 60
Glu His Gly Ile Val Thr Asn Trp Asp Asp Met Glu Lys Ile Trp His 65
70 75 80 His Thr Phe Tyr Asn
Glu Leu Arg Val Ala Pro Glu Glu His Pro Val 85
90 95 Leu Leu Thr Glu Ala Pro Leu Asn Pro Lys
Ala Asn Arg Glu Lys Met 100 105
110 Thr Gln Ile Met Phe Glu Thr Phe Asn Thr Pro Ala Met Tyr Val
Ala 115 120 125 Ile
Gln Ala Val Leu Ser Leu Tyr Ala Ser Gly Arg Thr Thr Gly Ile 130
135 140 Val Met Asp Ser Gly Asp
Gly Val Thr His Thr Val Pro Ile Tyr Glu 145 150
155 160 Gly Tyr Ala Leu Pro His Ala Ile Leu Arg Leu
Asp Leu Ala Gly Arg 165 170
175 Asp Leu Thr Asp Tyr Leu Met Lys Ile Leu Thr Glu Arg Gly Tyr Ser
180 185 190 Phe Thr
Thr Thr Ala Glu Arg Glu Ile Val Arg Asp Ile Lys Glu Lys 195
200 205 Leu Cys Tyr Val Ala Leu Asp
Phe Glu Gln Glu Met Ala Thr Ala Ala 210 215
220 Ser Ser Ser Ser Leu Glu Lys Ser Tyr Glu Leu Pro
Asp Gly Gln Val 225 230 235
240 Ile Thr Ile Gly Asn Glu Arg Phe Arg Cys Pro Glu Ala Leu Phe Gln
245 250 255 Pro Ser Phe
Leu Gly Met Glu Ser Cys Gly Ile His Glu Thr Thr Phe 260
265 270 Asn Ser Ile Met Lys Cys Asp Val
Asp Ile Arg Lys Asp Leu Tyr Ala 275 280
285 Asn Thr Val Leu Ser Gly Gly Thr Thr Met Tyr Pro Gly
Ile Ala Asp 290 295 300
Arg Met Gln Lys Glu Ile Thr Ala Leu Ala Pro Ser Thr Met Lys Ile 305
310 315 320 Lys Ile Ile Ala
Pro Pro Glu Arg Lys Tyr Ser Val Trp Ile Gly Gly 325
330 335 Ser Ile Leu Ala Ser Leu Ser Thr Phe
Gln Gln Met Trp Ile Ser Lys 340 345
350 Gln Glu Tyr Asp Glu Ser Gly Pro Ser Ile Val His Arg Lys
Cys Phe 355 360 365
34146PRTMus musculus 34Met Ala Gly Trp Gln Ser Tyr Val Asp Asn Leu Met
Cys Asp Gly Cys 1 5 10
15 Cys Gln Glu Ala Ala Ile Val Gly Tyr Cys Asp Ala Lys Tyr Val Trp
20 25 30 Ala Ala Thr
Ala Gly Gly Val Phe Gln Ser Ile Thr Pro Val Glu Ile 35
40 45 Asp Met Ile Val Gly Lys Asp Arg
Glu Gly Phe Phe Thr Asn Gly Leu 50 55
60 Thr Leu Gly Ala Lys Lys Cys Ser Val Ile Arg Asp Ser
Leu Tyr Val 65 70 75
80 Asp Gly Asp Cys Thr Met Asp Ile Arg Thr Lys Ser Gln Gly Gly Glu
85 90 95 Pro Thr Tyr Asn
Val Ala Val Gly Arg Ala Gly Arg Ala Leu Val Ile 100
105 110 Val Met Gly Lys Glu Gly Val His Ala
Gly Thr Ile Asn Lys Lys Thr 115 120
125 Tyr Glu Leu Ala Leu Tyr Leu Lys Arg Ser Val Thr Asn Leu
Tyr Leu 130 135 140
Ala Ser 145 35199PRTMus musculus 35Met Ala Asn Arg Gly Pro Ser Tyr
Gly Leu Ser Arg Glu Val Gln Glu 1 5 10
15 Lys Ile Glu Gln Lys Tyr Asp Ala Asp Leu Glu Asn Lys
Leu Val Asp 20 25 30
Trp Ile Ile Leu Gln Cys Ala Glu Asp Ile Glu His Pro Pro Pro Gly
35 40 45 Arg Ala His Phe
Gln Lys Trp Leu Met Asp Gly Thr Val Leu Cys Lys 50
55 60 Leu Ile Asn Ser Leu Tyr Pro Pro
Gly Gln Glu Pro Ile Pro Lys Ile 65 70
75 80 Ser Glu Ser Lys Met Ala Phe Lys Gln Met Glu Gln
Ile Ser Gln Phe 85 90
95 Leu Lys Ala Ala Glu Val Tyr Gly Val Arg Thr Thr Asp Ile Phe Gln
100 105 110 Thr Val Asp
Leu Trp Glu Gly Lys Asp Met Ala Ala Val Gln Arg Thr 115
120 125 Leu Met Ala Leu Gly Ser Val Ala
Val Thr Lys Asp Asp Gly Cys Tyr 130 135
140 Arg Gly Glu Pro Ser Trp Phe His Arg Lys Ala Gln Gln
Asn Arg Arg 145 150 155
160 Gly Phe Ser Glu Glu Gln Leu Arg Gln Gly Gln Asn Val Ile Gly Leu
165 170 175 Gln Met Gly Ser
Asn Lys Gly Ala Ser Gln Ala Gly Met Thr Gly Tyr 180
185 190 Gly Met Pro Arg Gln Ile Met
195 36677PRTMus musculus 36Arg Val Val Ser Ala Ala Glu
Pro Glu Thr Met Ala Lys Ile Ala Gln 1 5
10 15 Gly Ala Met Tyr Arg Gly Ser Val His Asp Phe
Pro Glu Phe Asp Ala 20 25
30 Asn Gln Asp Ala Glu Ala Leu Tyr Thr Ala Met Lys Gly Phe Gly
Ser 35 40 45 Asp
Lys Glu Ser Ile Leu Glu Leu Ile Thr Ser Arg Ser Asn Lys Gln 50
55 60 Arg Gln Glu Ile Cys Gln
Asn Tyr Lys Ser Leu Tyr Gly Lys Asp Leu 65 70
75 80 Ile Glu Asp Leu Lys Tyr Glu Leu Thr Gly Lys
Phe Glu Arg Leu Ile 85 90
95 Val Asn Leu Met Arg Pro Leu Ala Tyr Cys Asp Ala Lys Glu Ile Lys
100 105 110 Asp Ala
Ile Ser Gly Ile Gly Thr Asp Glu Lys Cys Leu Ile Glu Ile 115
120 125 Leu Ala Ser Arg Thr Asn Glu
Gln Met His Gln Leu Val Ala Ala Tyr 130 135
140 Lys Asp Ala Tyr Glu Arg Asp Leu Glu Ser Asp Ile
Ile Gly Asp Thr 145 150 155
160 Ser Gly His Phe Gln Lys Met Leu Val Val Leu Leu Gln Gly Thr Arg
165 170 175 Glu Asn Asp
Asp Val Val Ser Glu Asp Leu Val Gln Gln Asp Val Gln 180
185 190 Asp Leu Tyr Glu Ala Gly Glu Leu
Lys Trp Gly Thr Asp Glu Ala Gln 195 200
205 Phe Ile Tyr Ile Leu Gly Asn Arg Ser Lys Gln His Leu
Arg Leu Val 210 215 220
Phe Asp Glu Tyr Leu Lys Thr Thr Gly Lys Pro Ile Glu Ala Ser Ile 225
230 235 240 Arg Gly Glu Leu
Ser Gly Asp Phe Glu Lys Leu Met Leu Ala Val Val 245
250 255 Lys Cys Ile Arg Ser Thr Pro Glu Tyr
Phe Ala Glu Arg Leu Phe Lys 260 265
270 Ala Met Lys Gly Leu Gly Thr Arg Asp Asn Thr Leu Ile Arg
Ile Met 275 280 285
Val Ser Arg Ser Glu Leu Asp Met Leu Asp Ile Arg Glu Ile Phe Arg 290
295 300 Thr Lys Tyr Glu Lys
Ser Leu Tyr Ser Met Ile Lys Asn Asp Thr Ser 305 310
315 320 Gly Glu Tyr Lys Lys Ala Leu Leu Lys Leu
Cys Gly Gly Asp Asp Asp 325 330
335 Ala Ala Gly Gln Phe Phe Pro Glu Ala Ala Gln Val Ala Tyr Gln
Met 340 345 350 Trp
Glu Leu Ser Ala Val Ser Arg Val Glu Leu Lys Gly Thr Val Cys 355
360 365 Ala Ala Asn Asp Phe Asn
Pro Asp Ala Asp Ala Lys Ala Leu Arg Lys 370 375
380 Ala Met Lys Gly Ile Gly Thr Asp Glu Ala Thr
Ile Ile Asp Ile Val 385 390 395
400 Thr His Arg Ser Asn Ala Gln Arg Gln Gln Ile Arg Gln Thr Phe Lys
405 410 415 Ser His
Phe Gly Arg Asp Leu Met Ala Asp Leu Lys Ser Glu Ile Ser 420
425 430 Gly Asp Leu Ala Arg Leu Ile
Leu Gly Leu Met Met Pro Pro Ala His 435 440
445 Tyr Asp Ala Lys Gln Leu Lys Lys Ala Met Glu Gly
Ala Gly Thr Asp 450 455 460
Glu Lys Thr Leu Ile Glu Ile Leu Ala Thr Arg Thr Asn Ala Glu Ile 465
470 475 480 Arg Ala Ile
Asn Glu Ala Tyr Lys Glu Asp Tyr His Lys Ser Leu Glu 485
490 495 Asp Ala Leu Ser Ser Asp Thr Ser
Gly His Phe Arg Arg Ile Leu Ile 500 505
510 Ser Leu Ala Thr Gly Asn Arg Glu Glu Gly Gly Glu Asn
Arg Asp Gln 515 520 525
Ala Gln Glu Asp Ala Gln Glu Ile Ala Asp Thr Pro Ser Gly Asp Lys 530
535 540 Thr Ser Leu Glu
Thr Arg Phe Met Thr Val Leu Cys Thr Arg Ser Tyr 545 550
555 560 Pro His Leu Arg Arg Val Phe Gln Glu
Phe Ile Lys Lys Thr Asn Tyr 565 570
575 Asp Ile Glu His Val Ile Lys Lys Glu Met Ser Gly Asp Val
Lys Asp 580 585 590
Ala Phe Val Ala Ile Val Gln Ser Val Lys Asn Lys Pro Leu Phe Phe
595 600 605 Ala Asp Lys Leu
Tyr Lys Ser Met Lys Gly Ala Gly Thr Asp Glu Lys 610
615 620 Thr Leu Thr Arg Val Met Val Ser
Arg Ser Glu Ile Asp Leu Leu Asn 625 630
635 640 Ile Arg Arg Glu Phe Ile Glu Lys Tyr Asp Lys Ser
Leu His Gln Ala 645 650
655 Ile Glu Gly Asp Thr Ser Gly Asp Phe Met Lys Ala Leu Leu Ala Leu
660 665 670 Cys Gly Gly
Glu Asp 675 37501PRTMus musculus 37Met Ser Phe Gly Ser
Glu His Tyr Leu Cys Ser Ala Ser Ser Tyr Arg 1 5
10 15 Lys Val Phe Gly Asp Ser Ser Arg Leu Ser
Ala Arg Leu Ser Gly Pro 20 25
30 Gly Gly Ser Gly Ser Phe Arg Ser Gln Ser Leu Ser Arg Ser Asn
Val 35 40 45 Ala
Ser Thr Ala Ala Cys Ser Ser Ala Ser Ser Leu Gly Leu Gly Leu 50
55 60 Ala Tyr Arg Arg Leu Pro
Ala Ser Asp Gly Leu Asp Leu Ser Gln Ala 65 70
75 80 Ala Ala Arg Thr Asn Glu Tyr Lys Ile Ile Arg
Thr Asn Glu Lys Glu 85 90
95 Gln Leu Gln Gly Leu Asn Asp Arg Phe Ala Val Phe Ile Glu Lys Val
100 105 110 His Gln
Leu Glu Thr Gln Asn Arg Ala Leu Glu Ala Glu Leu Ala Ala 115
120 125 Leu Arg Gln Arg His Ala Glu
Pro Ser Arg Val Gly Glu Leu Phe Gln 130 135
140 Arg Glu Leu Arg Glu Leu Arg Ala Gln Leu Glu Glu
Ala Ser Ser Ala 145 150 155
160 Arg Ala Gln Ala Leu Leu Glu Arg Asp Gly Leu Ala Glu Glu Val Gln
165 170 175 Arg Leu Arg
Ala Arg Cys Glu Glu Glu Ser Arg Gly Arg Glu Gly Ala 180
185 190 Glu Arg Ala Leu Lys Ala Gln Gln
Arg Asp Val Asp Gly Ala Thr Leu 195 200
205 Ala Arg Leu Asp Leu Glu Lys Lys Val Glu Ser Leu Leu
Asp Glu Leu 210 215 220
Ala Phe Val Arg Gln Val His Asp Glu Glu Val Ala Glu Leu Leu Ala 225
230 235 240 Thr Leu Gln Ala
Ser Ser Gln Ala Ala Ala Glu Val Asp Val Ala Val 245
250 255 Ala Lys Pro Asp Leu Thr Ser Ala Leu
Arg Glu Ile Arg Ala Gln Tyr 260 265
270 Glu Ser Leu Ala Ala Lys Asn Leu Gln Ser Ala Glu Glu Trp
Tyr Lys 275 280 285
Ser Lys Phe Ala Asn Leu Asn Glu Gln Ala Ala Arg Ser Thr Glu Ala 290
295 300 Ile Arg Ala Ser Arg
Glu Glu Ile His Glu Tyr Arg Arg Gln Leu Gln 305 310
315 320 Ala Arg Thr Ile Glu Ile Glu Gly Leu Arg
Gly Ala Asn Glu Ser Leu 325 330
335 Glu Arg Gln Ile Leu Glu Leu Glu Glu Arg His Ser Ala Glu Val
Ala 340 345 350 Gly
Tyr Gln Asp Ser Ile Gly Gln Leu Glu Ser Asp Leu Arg Asn Thr 355
360 365 Lys Ser Glu Met Ala Arg
His Leu Arg Glu Tyr Gln Asp Leu Leu Asn 370 375
380 Val Lys Met Ala Leu Asp Ile Glu Ile Ala Ala
Tyr Arg Lys Leu Leu 385 390 395
400 Glu Gly Glu Glu Thr Arg Phe Ser Thr Gly Gly Leu Ser Ile Ser Gly
405 410 415 Leu Asn
Pro Leu Pro Asn Pro Ser Tyr Leu Leu Pro Pro Arg Ile Leu 420
425 430 Ser Ser Thr Ala Ser Lys Val
Ser Ser Ala Gly Leu Ser Leu Lys Lys 435 440
445 Glu Glu Glu Glu Glu Glu Glu Glu Ala Ser Lys Glu
Val Ser Lys Lys 450 455 460
Thr Ser Lys Val Gly Glu Gly Phe Glu Glu Thr Leu Gly Glu Ala Val 465
470 475 480 Ile Ser Thr
Lys Lys Thr Gly Lys Ser Ala Thr Glu Glu Ser Thr Ser 485
490 495 Ser Ser Gln Lys Met
500 38543PRTMus musculus 38Met Ser Ser Phe Gly Tyr Asp Pro Tyr Phe
Ser Thr Ser Tyr Lys Arg 1 5 10
15 Arg Tyr Val Glu Thr Pro Arg Val His Ile Ser Ser Val Arg Ser
Gly 20 25 30 Tyr
Ser Thr Ala Arg Ser Ala Tyr Ser Ser Tyr Ser Ala Pro Val Ser 35
40 45 Ser Ser Leu Ser Val Arg
Arg Ser Tyr Ser Ser Ser Ser Gly Ser Leu 50 55
60 Met Pro Ser Leu Glu Asn Leu Asp Leu Ser Gln
Val Ala Ala Ile Ser 65 70 75
80 Asn Asp Leu Lys Ser Ile Arg Thr Gln Glu Lys Ala Gln Leu Gln Asp
85 90 95 Leu Asn
Asp Arg Phe Ala Ser Phe Ile Glu Arg Val His Glu Leu Glu 100
105 110 Gln Gln Asn Lys Val Leu Glu
Ala Glu Leu Leu Val Leu Arg Gln Lys 115 120
125 His Ser Glu Pro Ser Arg Phe Arg Ala Leu Tyr Glu
Gln Glu Ile Arg 130 135 140
Asp Leu Arg Leu Ala Ala Glu Asp Ala Thr Asn Glu Lys Gln Ala Leu 145
150 155 160 Gln Gly Glu
Arg Glu Gly Leu Glu Glu Thr Leu Arg Asn Leu Gln Ala 165
170 175 Arg Tyr Glu Glu Glu Val Leu Ser
Arg Glu Asp Ala Glu Gly Arg Leu 180 185
190 Met Glu Ala Arg Lys Gly Ala Asp Glu Ala Ala Leu Ala
Arg Ala Glu 195 200 205
Leu Glu Lys Arg Ile Asp Ser Leu Met Asp Glu Ile Ala Phe Leu Lys 210
215 220 Lys Val His Glu
Glu Glu Ile Ala Glu Leu Gln Ala Gln Ile Gln Tyr 225 230
235 240 Ala Gln Ile Ser Val Glu Met Asp Val
Ser Ser Lys Pro Asp Leu Ser 245 250
255 Ala Ala Leu Lys Asp Ile Arg Ala Gln Tyr Glu Lys Leu Ala
Ala Lys 260 265 270
Asn Met Gln Asn Ala Glu Glu Trp Phe Lys Ser Arg Phe Thr Val Leu
275 280 285 Thr Glu Ser Ala
Ala Lys Asn Thr Asp Ala Val Arg Ala Ala Lys Asp 290
295 300 Glu Val Ser Glu Ser Arg Arg Leu
Leu Lys Ala Lys Thr Leu Glu Ile 305 310
315 320 Glu Ala Cys Arg Gly Met Asn Glu Ala Leu Glu Lys
Gln Leu Gln Glu 325 330
335 Leu Glu Asp Lys Gln Asn Ala Asp Ile Ser Ala Met Gln Asp Thr Ile
340 345 350 Asn Lys Leu
Glu Asn Glu Leu Arg Ser Thr Lys Ser Glu Met Ala Arg 355
360 365 Tyr Leu Lys Glu Tyr Gln Asp Leu
Leu Asn Val Lys Met Ala Leu Asp 370 375
380 Ile Glu Ile Ala Ala Tyr Arg Lys Leu Leu Glu Gly Glu
Glu Thr Arg 385 390 395
400 Leu Ser Phe Thr Ser Val Gly Ser Ile Thr Ser Gly Tyr Ser Gln Ser
405 410 415 Ser Gln Val Phe
Gly Arg Ser Ala Tyr Ser Gly Leu Gln Ser Ser Ser 420
425 430 Tyr Leu Met Ser Ala Arg Ser Phe Pro
Ala Tyr Tyr Thr Ser His Val 435 440
445 Gln Glu Glu Gln Thr Glu Val Glu Glu Thr Ile Glu Ala Thr
Lys Ala 450 455 460
Glu Glu Ala Lys Asp Glu Pro Pro Ser Glu Gly Glu Ala Glu Glu Glu 465
470 475 480 Glu Lys Glu Lys Glu
Glu Gly Glu Glu Glu Glu Gly Ala Glu Glu Glu 485
490 495 Glu Ala Ala Lys Asp Glu Ser Glu Asp Thr
Lys Glu Glu Glu Glu Gly 500 505
510 Gly Glu Gly Glu Glu Glu Asp Thr Lys Glu Ser Glu Glu Glu Glu
Lys 515 520 525 Lys
Glu Glu Ser Ala Gly Glu Glu Gln Val Ala Lys Lys Lys Asp 530
535 540 39400PRTMus musculus 39Met Pro
Arg Phe Ser Leu Ser Arg Met Thr Pro Pro Leu Pro Ala Arg 1 5
10 15 Val Asp Phe Ser Leu Ala Gly
Ala Leu Asn Ala Gly Phe Lys Glu Thr 20 25
30 Arg Ala Ser Glu Arg Ala Glu Met Met Glu Leu Asn
Asp Arg Phe Ala 35 40 45
Ser Tyr Ile Glu Lys Val Arg Phe Leu Glu Gln Gln Asn Lys Ala Leu
50 55 60 Ala Ala Glu
Leu Asn Gln Leu Arg Ala Lys Glu Pro Thr Lys Leu Ala 65
70 75 80 Asp Val Tyr Gln Ala Glu Leu
Arg Glu Leu Arg Leu Arg Leu Asp Gln 85
90 95 Leu Thr Ala Asn Ser Ala Arg Leu Glu Val Glu
Arg Asp Asn Phe Ala 100 105
110 Gln Asp Leu Gly Thr Leu Arg Gln Lys Leu Gln Asp Glu Thr Asn
Leu 115 120 125 Arg
Leu Glu Ala Glu Asn Asn Leu Ala Ala Tyr Arg Gln Glu Ala Asp 130
135 140 Glu Ala Thr Leu Ala Arg
Val Asp Leu Glu Arg Lys Val Glu Ser Leu 145 150
155 160 Glu Glu Glu Ile Gln Phe Leu Arg Lys Ile Tyr
Glu Glu Glu Val Arg 165 170
175 Glu Leu Arg Glu Gln Leu Ala Gln Gln Gln Val His Val Glu Met Asp
180 185 190 Val Ala
Lys Pro Asp Leu Thr Ala Ala Leu Arg Glu Ile Arg Thr Gln 195
200 205 Tyr Glu Ala Val Ala Thr Ser
Asn Met Gln Glu Thr Glu Glu Trp Tyr 210 215
220 Arg Ser Lys Phe Ala Asp Leu Thr Asp Ala Ala Ser
Arg Asn Ala Glu 225 230 235
240 Leu Leu Arg Gln Ala Lys His Glu Ala Asn Asp Tyr Arg Arg Gln Leu
245 250 255 Gln Ala Leu
Thr Cys Asp Leu Glu Ser Leu Arg Gly Thr Asn Glu Ser 260
265 270 Leu Glu Arg Gln Met Arg Glu Gln
Glu Glu Arg His Ala Arg Glu Ser 275 280
285 Ala Ser Tyr Gln Glu Ala Leu Ala Arg Leu Glu Glu Glu
Gly Gln Ser 290 295 300
Leu Lys Glu Glu Met Ala Arg His Leu Gln Glu Tyr Gln Asp Leu Leu 305
310 315 320 Asn Val Lys Leu
Ala Leu Asp Ile Glu Ile Ala Thr Tyr Arg Lys Leu 325
330 335 Leu Glu Gly Glu Glu Asn Arg Ile Thr
Ile Pro Val Gln Thr Phe Ser 340 345
350 Asn Leu Gln Ile Arg Glu Thr Ser Leu Asp Thr Lys Ser Val
Ser Glu 355 360 365
Gly His Leu Lys Arg Asn Ile Val Val Lys Thr Val Glu Met Arg Asp 370
375 380 Gly Glu Val Ile Lys
Asp Ser Lys Gln Glu His Lys Asp Val Val Met 385 390
395 400 40451PRTMus musculus 40Met Arg Glu Cys
Ile Ser Ile His Val Gly Gln Ala Gly Val Gln Ile 1 5
10 15 Gly Asn Ala Cys Trp Glu Leu Tyr Cys
Leu Glu His Gly Ile Gln Pro 20 25
30 Asp Gly Gln Met Pro Ser Asp Lys Thr Ile Gly Gly Gly Asp
Asp Ser 35 40 45
Phe Asn Thr Phe Phe Ser Glu Thr Gly Ala Gly Lys His Val Pro Arg 50
55 60 Ala Val Phe Val Asp
Leu Glu Pro Thr Val Ile Asp Glu Val Arg Thr 65 70
75 80 Gly Thr Tyr Arg Gln Leu Phe His Pro Glu
Gln Leu Ile Thr Gly Lys 85 90
95 Glu Asp Ala Ala Asn Asn Tyr Ala Arg Gly His Tyr Thr Ile Gly
Lys 100 105 110 Glu
Ile Ile Asp Leu Val Leu Asp Arg Ile Arg Lys Leu Ala Asp Gln 115
120 125 Cys Thr Gly Leu Gln Gly
Phe Leu Val Phe His Ser Phe Gly Gly Gly 130 135
140 Thr Gly Ser Gly Phe Thr Ser Leu Leu Met Glu
Arg Leu Ser Val Asp 145 150 155
160 Tyr Gly Lys Lys Ser Lys Leu Glu Phe Ser Ile Tyr Pro Ala Pro Gln
165 170 175 Val Ser
Thr Ala Val Val Glu Pro Tyr Asn Ser Ile Leu Thr Thr His 180
185 190 Thr Thr Leu Glu His Ser Asp
Cys Ala Phe Met Val Asp Asn Glu Ala 195 200
205 Ile Tyr Asp Ile Cys Arg Arg Asn Leu Asp Ile Glu
Arg Pro Thr Tyr 210 215 220
Thr Asn Leu Asn Arg Leu Ile Ser Gln Ile Val Ser Ser Ile Thr Ala 225
230 235 240 Ser Leu Arg
Phe Asp Gly Ala Leu Asn Val Asp Leu Thr Glu Phe Gln 245
250 255 Thr Asn Leu Val Pro Tyr Pro Arg
Ile His Phe Pro Leu Ala Thr Tyr 260 265
270 Ala Pro Val Ile Ser Ala Glu Lys Ala Tyr His Glu Gln
Leu Ser Val 275 280 285
Ala Glu Ile Thr Asn Ala Cys Phe Glu Pro Ala Asn Gln Met Val Lys 290
295 300 Cys Asp Pro Arg
His Gly Lys Tyr Met Ala Cys Cys Leu Leu Tyr Arg 305 310
315 320 Gly Asp Val Val Pro Lys Asp Val Asn
Ala Ala Ile Ala Thr Ile Lys 325 330
335 Thr Lys Arg Ser Ile Gln Phe Val Asp Trp Cys Pro Thr Gly
Phe Lys 340 345 350
Val Gly Ile Asn Tyr Gln Pro Pro Thr Val Val Pro Gly Gly Asp Leu
355 360 365 Ala Lys Val Gln
Arg Ala Val Cys Met Leu Ser Asn Thr Thr Ala Ile 370
375 380 Ala Glu Ala Trp Ala Arg Leu Asp
His Lys Phe Asp Leu Met Tyr Ala 385 390
395 400 Lys Arg Ala Phe Val His Trp Tyr Val Gly Glu Gly
Met Glu Glu Gly 405 410
415 Glu Phe Ser Glu Ala Arg Glu Asp Met Ala Ala Leu Glu Lys Asp Tyr
420 425 430 Glu Glu Val
Gly Val Asp Ser Val Glu Gly Glu Gly Glu Glu Glu Gly 435
440 445 Glu Glu Tyr 450
41445PRTMus musculus 41Met Arg Glu Ile Val His Ile Gln Ala Gly Gln Cys
Gly Asn Gln Ile 1 5 10
15 Gly Ala Lys Phe Trp Glu Val Ile Ser Asp Glu His Gly Ile Asp Pro
20 25 30 Thr Gly Ser
Tyr His Gly Asp Ser Asp Leu Gln Leu Glu Arg Ile Asn 35
40 45 Val Tyr Tyr Asn Glu Ala Thr Gly
Asn Lys Tyr Val Pro Arg Ala Ile 50 55
60 Leu Val Asp Leu Glu Pro Gly Thr Met Asp Ser Val Arg
Ser Gly Pro 65 70 75
80 Phe Gly Gln Ile Phe Arg Pro Asp Asn Phe Val Phe Gly Gln Ser Gly
85 90 95 Ala Gly Asn Asn
Trp Ala Lys Gly His Tyr Thr Glu Gly Ala Glu Leu 100
105 110 Val Asp Ser Val Leu Asp Val Val Arg
Lys Glu Ser Glu Ser Cys Asp 115 120
125 Cys Leu Gln Gly Phe Gln Leu Thr His Ser Leu Gly Gly Gly
Thr Gly 130 135 140
Ser Gly Met Gly Thr Leu Leu Ile Ser Lys Ile Arg Glu Glu Tyr Pro 145
150 155 160 Asp Arg Ile Met Asn
Thr Phe Ser Val Met Pro Ser Pro Lys Val Ser 165
170 175 Asp Thr Val Val Glu Pro Tyr Asn Ala Thr
Leu Ser Val His Gln Leu 180 185
190 Val Glu Asn Thr Asp Glu Thr Tyr Cys Ile Asp Asn Glu Ala Leu
Tyr 195 200 205 Asp
Ile Cys Phe Arg Thr Leu Lys Leu Thr Thr Pro Thr Tyr Gly Asp 210
215 220 Leu Asn His Leu Val Ser
Ala Thr Met Ser Gly Val Thr Thr Cys Leu 225 230
235 240 Arg Phe Pro Gly Gln Leu Asn Ala Asp Leu Arg
Lys Leu Ala Val Asn 245 250
255 Met Val Pro Phe Pro Arg Leu His Phe Phe Met Pro Gly Phe Ala Pro
260 265 270 Leu Thr
Ser Arg Gly Ser Gln Gln Tyr Arg Ala Leu Thr Val Pro Glu 275
280 285 Leu Thr Gln Gln Met Phe Asp
Ser Lys Asn Met Met Ala Ala Cys Asp 290 295
300 Pro Arg His Gly Arg Tyr Leu Thr Val Ala Ala Ile
Phe Arg Gly Arg 305 310 315
320 Met Ser Met Lys Glu Val Asp Glu Gln Met Leu Asn Val Gln Asn Lys
325 330 335 Asn Ser Ser
Tyr Phe Val Glu Trp Ile Pro Asn Asn Val Lys Thr Ala 340
345 350 Val Cys Asp Ile Pro Pro Arg Gly
Leu Lys Met Ser Ala Thr Phe Ile 355 360
365 Gly Asn Ser Thr Ala Ile Gln Glu Leu Phe Lys Arg Ile
Ser Glu Gln 370 375 380
Phe Thr Ala Met Phe Arg Arg Lys Ala Phe Leu His Trp Tyr Thr Gly 385
390 395 400 Glu Gly Met Asp
Glu Met Glu Phe Thr Glu Ala Glu Ser Asn Met Asn 405
410 415 Asp Leu Val Ser Glu Tyr Gln Gln Tyr
Gln Asp Ala Thr Ala Asp Glu 420 425
430 Gln Gly Glu Phe Glu Glu Glu Glu Gly Glu Asp Glu Ala
435 440 445 42450PRTMus musculus
42Met Arg Glu Ile Val His Ile Gln Ala Gly Gln Cys Gly Asn Gln Ile 1
5 10 15 Gly Ala Lys Phe
Trp Glu Val Ile Ser Asp Glu His Gly Ile Asp Pro 20
25 30 Ser Gly Asn Tyr Val Gly Asp Ser Asp
Leu Gln Leu Glu Arg Ile Ser 35 40
45 Val Tyr Tyr Asn Glu Ala Ser Ser His Lys Tyr Val Pro Arg
Ala Ile 50 55 60
Leu Val Asp Leu Glu Pro Gly Thr Met Asp Ser Val Arg Ser Gly Ala 65
70 75 80 Phe Gly His Leu Phe
Arg Pro Asp Asn Phe Ile Phe Gly Gln Ser Gly 85
90 95 Ala Gly Asn Asn Trp Ala Lys Gly His Tyr
Thr Glu Gly Ala Glu Leu 100 105
110 Val Asp Ser Val Leu Asp Val Val Arg Lys Glu Cys Glu Asn Cys
Asp 115 120 125 Cys
Leu Gln Gly Phe Gln Leu Thr His Ser Leu Gly Gly Gly Thr Gly 130
135 140 Ser Gly Met Gly Thr Leu
Leu Ile Ser Lys Val Arg Glu Glu Tyr Pro 145 150
155 160 Asp Arg Ile Met Asn Thr Phe Ser Val Val Pro
Ser Pro Lys Val Ser 165 170
175 Asp Thr Val Val Glu Pro Tyr Asn Ala Thr Leu Ser Ile His Gln Leu
180 185 190 Val Glu
Asn Thr Asp Glu Thr Tyr Cys Ile Asp Asn Glu Ala Leu Tyr 195
200 205 Asp Ile Cys Phe Arg Thr Leu
Lys Leu Ala Thr Pro Thr Tyr Gly Asp 210 215
220 Leu Asn His Leu Val Ser Ala Thr Met Ser Gly Val
Thr Thr Ser Leu 225 230 235
240 Arg Phe Pro Gly Gln Leu Asn Ala Asp Leu Arg Lys Leu Ala Val Asn
245 250 255 Met Val Pro
Phe Pro Arg Leu His Phe Phe Met Pro Gly Phe Ala Pro 260
265 270 Leu Thr Ala Arg Gly Ser Gln Gln
Tyr Arg Ala Leu Thr Val Pro Glu 275 280
285 Leu Thr Gln Gln Met Phe Asp Ala Lys Asn Met Met Ala
Ala Cys Asp 290 295 300
Pro Arg His Gly Arg Tyr Leu Thr Val Ala Thr Val Phe Arg Gly Arg 305
310 315 320 Met Ser Met Lys
Glu Val Asp Glu Gln Met Leu Ala Ile Gln Ser Lys 325
330 335 Asn Ser Ser Tyr Phe Val Glu Trp Ile
Pro Asn Asn Val Lys Val Ala 340 345
350 Val Cys Asp Ile Pro Pro Arg Gly Leu Lys Met Ser Ser Thr
Phe Ile 355 360 365
Gly Asn Ser Thr Ala Ile Gln Glu Leu Phe Lys Arg Ile Ser Glu Gln 370
375 380 Phe Thr Ala Met Phe
Arg Arg Lys Ala Phe Leu His Trp Tyr Thr Gly 385 390
395 400 Glu Gly Met Asp Glu Met Glu Phe Thr Glu
Ala Glu Ser Asn Met Asn 405 410
415 Asp Leu Val Ser Glu Tyr Gln Gln Tyr Gln Asp Ala Thr Ala Glu
Glu 420 425 430 Glu
Gly Glu Met Tyr Glu Asp Asp Asp Glu Glu Ser Glu Ala Gln Gly 435
440 445 Pro Lys 450
43572PRTMus musculus 43Met Ser Tyr Gln Gly Lys Lys Asn Ile Pro Arg Ile
Thr Ser Asp Arg 1 5 10
15 Leu Leu Ile Lys Gly Gly Lys Ile Val Asn Asp Asp Gln Ser Phe Tyr
20 25 30 Ala Asp Ile
Tyr Met Glu Asp Gly Leu Ile Lys Gln Ile Gly Glu Asn 35
40 45 Leu Ile Val Pro Gly Gly Val Lys
Thr Ile Glu Ala His Ser Arg Met 50 55
60 Val Ile Pro Gly Gly Ile Asp Val His Thr Arg Phe Gln
Met Pro Asp 65 70 75
80 Gln Gly Met Thr Ser Ala Asp Asp Phe Phe Gln Gly Thr Lys Ala Ala
85 90 95 Leu Ala Gly Gly
Thr Thr Met Ile Ile Asp His Val Val Pro Glu Pro 100
105 110 Gly Thr Ser Leu Leu Ala Ala Phe Asp
Gln Trp Arg Glu Trp Ala Asp 115 120
125 Ser Lys Ser Cys Cys Asp Tyr Ser Leu His Val Asp Ile Thr
Glu Trp 130 135 140
His Lys Gly Ile Gln Glu Glu Met Glu Ala Leu Val Lys Asp His Gly 145
150 155 160 Val Asn Ser Phe Leu
Val Tyr Met Ala Phe Lys Asp Arg Phe Gln Leu 165
170 175 Thr Asp Ser Gln Ile Tyr Glu Val Leu Ser
Val Ile Arg Asp Ile Gly 180 185
190 Ala Ile Ala Gln Val His Ala Glu Asn Gly Asp Ile Ile Ala Glu
Glu 195 200 205 Gln
Gln Arg Ile Leu Asp Leu Gly Ile Thr Gly Pro Glu Gly His Val 210
215 220 Leu Ser Arg Pro Glu Glu
Val Glu Ala Glu Ala Val Asn Arg Ser Ile 225 230
235 240 Thr Ile Ala Asn Gln Thr Asn Cys Pro Leu Tyr
Val Thr Lys Val Met 245 250
255 Ser Lys Ser Ala Ala Glu Val Ile Ala Gln Ala Arg Lys Lys Gly Thr
260 265 270 Val Val
Tyr Gly Glu Pro Ile Thr Ala Ser Leu Gly Thr Asp Gly Ser 275
280 285 His Tyr Trp Ser Lys Asn Trp
Ala Lys Ala Ala Ala Phe Val Thr Ser 290 295
300 Pro Pro Leu Ser Pro Asp Pro Thr Thr Pro Asp Phe
Leu Asn Ser Leu 305 310 315
320 Leu Ser Cys Gly Asp Leu Gln Val Thr Gly Ser Ala His Cys Thr Phe
325 330 335 Asn Thr Ala
Gln Lys Ala Val Gly Lys Asp Asn Phe Thr Leu Ile Pro 340
345 350 Glu Gly Thr Asn Gly Thr Glu Glu
Arg Met Ser Val Ile Trp Asp Lys 355 360
365 Ala Val Val Thr Gly Lys Met Asp Glu Asn Gln Phe Val
Ala Val Thr 370 375 380
Ser Thr Asn Ala Ala Lys Val Phe Asn Leu Tyr Pro Arg Lys Gly Arg 385
390 395 400 Ile Ser Val Gly
Ser Asp Ala Asp Leu Val Ile Trp Asp Pro Asp Ser 405
410 415 Val Lys Thr Ile Ser Ala Lys Thr His
Asn Ser Ala Leu Glu Tyr Asn 420 425
430 Ile Phe Glu Gly Met Glu Cys Arg Gly Ser Pro Leu Val Val
Ile Ser 435 440 445
Gln Gly Lys Ile Val Leu Glu Asp Gly Thr Leu His Val Thr Glu Gly 450
455 460 Ser Gly Arg Tyr Ile
Pro Arg Lys Pro Phe Pro Asp Phe Val Tyr Lys 465 470
475 480 Arg Ile Lys Ala Arg Ser Arg Leu Ala Glu
Leu Arg Gly Val Pro Arg 485 490
495 Gly Leu Tyr Asp Gly Pro Val Cys Glu Val Ser Val Thr Pro Lys
Thr 500 505 510 Val
Thr Pro Ala Ser Ser Ala Lys Thr Ser Pro Ala Lys Gln Gln Ala 515
520 525 Pro Pro Val Arg Asn Leu
His Gln Ser Gly Phe Ser Leu Ser Gly Ala 530 535
540 Gln Ile Asp Asp Asn Ile Pro Arg Arg Thr Thr
Gln Arg Ile Val Ala 545 550 555
560 Pro Pro Gly Gly Arg Ala Asn Ile Thr Ser Leu Gly
565 570 44365PRTMus musculus 44 Glu Gln Lys Arg
Leu Leu Glu Gln Gly Ile Thr Gly Pro Glu Gly His 1 5
10 15 Val Leu Ser His Pro Glu Glu Val Glu
Ala Glu Ala Val Tyr Arg Ala 20 25
30 Val Thr Ile Ala Lys Gln Ala Asn Cys Pro Leu Tyr Val Thr
Lys Val 35 40 45
Met Ser Lys Gly Ala Ala Asp Met Val Ala Gln Ala Lys Arg Arg Gly 50
55 60 Val Val Val Phe Gly
Glu Pro Ile Thr Ala Ser Leu Gly Thr Asp Gly 65 70
75 80 Ser His Tyr Trp Ser Lys Asn Trp Ala Lys
Ala Ala Ala Phe Val Thr 85 90
95 Ser Pro Pro Ile Asn Pro Asp Pro Thr Thr Ala Asp His Leu Thr
Ser 100 105 110 Leu
Leu Ser Ser Gly Asp Leu Gln Val Thr Gly Ser Ala His Cys Thr 115
120 125 Phe Thr Thr Ala Gln Lys
Ala Val Gly Lys Asp Asn Phe Thr Leu Ile 130 135
140 Pro Glu Gly Val Asn Gly Ile Glu Glu Arg Met
Ser Val Val Trp Glu 145 150 155
160 Lys Cys Val Ala Ser Gly Lys Met Asp Glu Asn Glu Phe Val Ala Val
165 170 175 Thr Ser
Thr Asn Ala Ala Lys Ile Phe Asn Phe Tyr Pro Arg Lys Gly 180
185 190 Arg Val Ala Val Gly Ser Asp
Ala Asp Leu Val Ile Trp Asn Pro Arg 195 200
205 Ala Thr Lys Val Ile Ser Ala Lys Ser His Asn Leu
Asn Val Glu Tyr 210 215 220
Asn Ile Phe Glu Gly Val Glu Cys Arg Gly Val Pro Thr Val Val Ile 225
230 235 240 Ser Gln Gly
Arg Val Val Leu Glu Asp Gly Asn Leu Leu Val Thr Pro 245
250 255 Gly Ala Gly Arg Phe Ile Pro Arg
Lys Thr Phe Pro Asp Phe Val Tyr 260 265
270 Lys Arg Ile Lys Ala Arg Asn Arg Leu Ala Glu Ile His
Gly Val Pro 275 280 285
Arg Gly Leu Tyr Asp Gly Pro Val His Glu Val Met Leu Pro Ala Lys 290
295 300 Pro Gly Ser Gly
Thr Gln Ala Arg Ala Ser Cys Ser Gly Lys Ile Ser 305 310
315 320 Val Pro Pro Val Arg Asn Leu His Gln
Ser Gly Phe Ser Leu Ser Gly 325 330
335 Ser Gln Ala Asp Asp His Ile Ala Arg Arg Thr Ala Gln Lys
Ile Met 340 345 350
Ala Pro Pro Gly Gly Arg Ser Asn Ile Thr Ser Leu Ser 355
360 365 45226PRTMus musculus 45Met Gly Gly Lys Leu
Ser Lys Lys Lys Lys Gly Tyr Asn Val Asn Asp 1 5
10 15 Glu Lys Ala Lys Asp Lys Asp Lys Lys Ala
Glu Gly Ala Gly Thr Glu 20 25
30 Glu Glu Gly Thr Pro Lys Glu Ser Glu Pro Gln Ala Ala Ala Asp
Ala 35 40 45 Thr
Glu Val Lys Glu Ser Thr Glu Glu Lys Pro Lys Asp Ala Ala Asp 50
55 60 Gly Glu Ala Lys Ala Glu
Glu Lys Glu Ala Asp Lys Ala Ala Ala Ala 65 70
75 80 Lys Glu Glu Ala Pro Lys Ala Glu Pro Glu Lys
Ser Glu Gly Ala Ala 85 90
95 Glu Glu Gln Pro Glu Pro Ala Pro Ala Pro Glu Gln Glu Ala Ala Ala
100 105 110 Pro Gly
Pro Ala Ala Gly Gly Glu Ala Pro Lys Ala Gly Glu Ala Ser 115
120 125 Ala Glu Ser Thr Gly Ala Ala
Asp Gly Ala Ala Pro Glu Glu Gly Glu 130 135
140 Ala Lys Lys Thr Glu Ala Pro Ala Ala Ala Gly Pro
Glu Ala Lys Ser 145 150 155
160 Asp Ala Ala Pro Ala Ala Ser Asp Ser Lys Pro Ser Ser Ala Glu Pro
165 170 175 Ala Pro Ser
Ser Lys Glu Thr Pro Ala Ala Ser Glu Ala Pro Ser Ser 180
185 190 Ala Ala Lys Ala Pro Ala Pro Ala
Ala Pro Ala Ala Ala Glu Pro Gln 195 200
205 Ala Glu Ala Pro Ala Ala Ala Ala Ser Ser Glu Gln Ser
Val Ala Val 210 215 220
Lys Glu 225 46189PRTMus musculus 46Met Asn Pro Glu Tyr Asp Tyr Leu
Phe Lys Leu Leu Leu Ile Gly Asp 1 5 10
15 Ser Gly Val Gly Lys Ser Cys Leu Leu Leu Arg Phe Ala
Asp Asp Thr 20 25 30
Tyr Thr Glu Ser Tyr Ile Ser Thr Ile Gly Val Asp Phe Lys Ile Arg
35 40 45 Thr Ile Glu Leu
Asp Gly Lys Thr Ile Lys Leu Gln Ile Trp Asp Thr 50
55 60 Ala Gly Gln Glu Arg Phe Arg Thr
Ile Thr Ser Ser Tyr Tyr Arg Gly 65 70
75 80 Ala His Gly Ile Ile Val Val Tyr Asp Val Thr Asp
Gln Glu Ser Tyr 85 90
95 Ala Asn Val Lys Gln Trp Leu Gln Glu Ile Asp Arg Tyr Ala Ser Glu
100 105 110 Asn Val Asn
Lys Leu Leu Val Gly Asn Lys Ser Asp Leu Thr Thr Lys 115
120 125 Lys Val Val Asp Asn Thr Thr Ala
Lys Val Ser Arg Pro Ala Leu Ala 130 135
140 Val Arg Gly Leu Gly Pro Thr Cys Leu His Pro Phe Ser
Pro Cys Ser 145 150 155
160 Pro Leu Ser Leu Leu Pro Phe Ala Gly Ile Cys Arg Leu Ser Gly Cys
165 170 175 Pro Leu Pro Arg
Asp Lys Cys Gln Glu Cys His Gln Cys 180 185
47220PRTMus musculus 47Met Ala Ser Ala Thr Asp Ser Arg Tyr
Gly Gln Lys Glu Ser Ser Asp 1 5 10
15 Gln Asn Phe Asp Tyr Met Phe Lys Ile Leu Ile Ile Gly Asn
Ser Ser 20 25 30
Val Gly Lys Thr Ser Phe Leu Phe Arg Tyr Ala Asp Asp Ser Phe Thr
35 40 45 Pro Ala Phe Val
Ser Thr Val Gly Ile Asp Phe Lys Val Lys Thr Ile 50
55 60 Tyr Arg Asn Asp Lys Arg Ile Lys
Leu Gln Ile Trp Asp Thr Ala Gly 65 70
75 80 Gln Glu Arg Tyr Arg Thr Ile Thr Thr Ala Tyr Tyr
Arg Gly Ala Met 85 90
95 Gly Phe Ile Leu Met Tyr Asp Ile Thr Asn Glu Glu Ser Phe Asn Ala
100 105 110 Val Gln Asp
Trp Ser Thr Gln Ile Lys Thr Tyr Ser Trp Asp Asn Ala 115
120 125 Gln Val Leu Leu Val Gly Asn Lys
Cys Asp Met Glu Asp Glu Arg Val 130 135
140 Val Ser Ser Glu Arg Gly Arg Gln Leu Ala Asp His Leu
Gly Phe Glu 145 150 155
160 Phe Phe Glu Ala Ser Ala Lys Asp Asn Ile Asn Val Lys Gln Thr Phe
165 170 175 Glu Arg Leu Val
Asp Val Ile Cys Glu Lys Met Ser Glu Ser Leu Asp 180
185 190 Thr Ala Asp Pro Ala Val Thr Gly Ala
Lys Gln Gly Pro Gln Leu Thr 195 200
205 Asp Gln Gln Ala Pro Pro His Gln Asp Cys Ala Cys 210
215 220 48208PRTMus musculus 48Met Ser
Ala Gly Gly Asp Phe Gly Asn Pro Leu Arg Lys Phe Lys Leu 1 5
10 15 Val Phe Leu Gly Glu Gln Ser
Val Gly Lys Thr Ser Leu Ile Thr Arg 20 25
30 Phe Met Tyr Asp Ser Phe Asp Asn Thr Tyr Gln Ala
Thr Ile Gly Ile 35 40 45
Asp Phe Leu Ser Lys Thr Met Tyr Leu Glu Asp Arg Thr Val Arg Leu
50 55 60 Gln Leu Trp
Asp Thr Ala Gly Gln Glu Arg Phe Arg Ser Leu Ile Pro 65
70 75 80 Ser Tyr Ile Arg Asp Ser Thr
Val Ala Val Val Val Tyr Asp Ile Thr 85
90 95 Asn Val Asn Ser Phe Gln Gln Thr Thr Lys Trp
Ile Asp Asp Val Arg 100 105
110 Thr Glu Arg Gly Ser Asp Val Ile Ile Met Leu Val Gly Asn Lys
Thr 115 120 125 Asp
Leu Ala Asp Lys Arg Gln Val Ser Ile Glu Glu Gly Glu Arg Lys 130
135 140 Ala Lys Glu Leu Asn Val
Met Phe Ile Glu Thr Ser Ala Lys Ala Gly 145 150
155 160 Tyr Asn Val Lys Gln Leu Phe Arg Arg Val Ala
Ala Ala Leu Pro Gly 165 170
175 Met Glu Ser Thr Gln Asp Arg Ser Arg Glu Asp Met Ile Asp Ile Lys
180 185 190 Leu Glu
Lys Pro Gln Glu Gln Pro Val Asn Glu Gly Gly Cys Ser Cys 195
200 205 49447PRTMus musculus 49Met
Asp Glu Glu Tyr Asp Val Ile Val Leu Gly Thr Gly Leu Thr Glu 1
5 10 15 Cys Ile Leu Ser Gly Ile
Met Ser Val Asn Gly Lys Lys Val Leu His 20
25 30 Met Asp Arg Asn Pro Tyr Tyr Gly Gly Glu
Ser Ser Ser Ile Thr Pro 35 40
45 Leu Glu Glu Leu Tyr Lys Arg Phe Gln Ile Leu Glu Gly Pro
Pro Glu 50 55 60
Ser Met Gly Arg Gly Arg Asp Trp Asn Val Asp Leu Ile Pro Lys Phe 65
70 75 80 Leu Met Ala Asn Gly
Gln Leu Val Lys Met Leu Leu Tyr Thr Glu Val 85
90 95 Thr Arg Tyr Leu Asp Phe Lys Val Val Glu
Gly Ser Phe Val Tyr Lys 100 105
110 Gly Gly Lys Ile Tyr Lys Val Pro Ser Thr Glu Thr Glu Ala Leu
Ala 115 120 125 Ser
Asn Leu Met Gly Met Phe Glu Lys Arg Arg Phe Arg Lys Phe Leu 130
135 140 Val Phe Val Ala Asn Phe
Asp Glu Asn Asp Pro Lys Thr Phe Glu Gly 145 150
155 160 Val Asp Pro Gln Asn Thr Ser Met Arg Asp Val
Tyr Arg Lys Phe Asp 165 170
175 Leu Gly Gln Asp Val Ile Asp Phe Thr Gly His Ala Leu Ala Leu Tyr
180 185 190 Arg Thr
Asp Asp Tyr Leu Asp Gln Pro Cys Leu Glu Thr Ile Asn Arg 195
200 205 Ile Lys Leu Tyr Ser Glu Ser
Leu Ala Arg Tyr Gly Lys Ser Pro Tyr 210 215
220 Leu Tyr Pro Leu Tyr Gly Leu Gly Glu Leu Pro Gln
Gly Phe Ala Arg 225 230 235
240 Leu Ser Ala Ile Tyr Gly Gly Thr Tyr Met Leu Asn Lys Pro Val Asp
245 250 255 Asp Ile Ile
Met Glu Asn Gly Lys Val Val Gly Val Lys Ser Glu Gly 260
265 270 Glu Val Ala Arg Cys Lys Gln Leu
Ile Cys Asp Pro Ser Tyr Ile Pro 275 280
285 Asp Arg Val Gln Lys Ala Gly Gln Val Ile Arg Ile Ile
Cys Ile Leu 290 295 300
Ser His Pro Ile Lys Asn Thr Asn Asp Ala Asn Ser Cys Gln Ile Ile 305
310 315 320 Ile Pro Gln Asn
Gln Val Asn Arg Lys Ser Asp Ile Tyr Val Cys Met 325
330 335 Ile Ser Tyr Ala His Asn Val Ala Ala
Gln Gly Lys Tyr Ile Ala Ile 340 345
350 Ala Ser Thr Thr Val Glu Thr Ala Glu Pro Glu Lys Glu Val
Glu Pro 355 360 365
Ala Leu Glu Leu Leu Glu Pro Ile Asp Gln Lys Phe Val Ala Ile Ser 370
375 380 Asp Leu Tyr Glu Pro
Ile Asp Asp Gly Ser Glu Ser Gln Val Phe Cys 385 390
395 400 Ser Cys Ser Tyr Asp Ala Thr Thr His Phe
Glu Thr Thr Cys Asn Asp 405 410
415 Ile Lys Asp Ile Tyr Lys Arg Met Ala Gly Ser Ala Phe Asp Phe
Glu 420 425 430 Asn
Met Lys Arg Lys Gln Asn Asp Val Phe Gly Glu Ala Asp Gln 435
440 445 50298PRTMus musculus 50Met Asp
Asn Ala Gly Lys Glu Arg Glu Ala Val Gln Leu Met Ala Glu 1 5
10 15 Ala Glu Lys Arg Val Lys Ala
Ser His Ser Phe Leu Arg Gly Leu Phe 20 25
30 Gly Gly Asn Thr Arg Ile Glu Glu Ala Cys Glu Met
Tyr Thr Arg Ala 35 40 45
Ala Asn Met Phe Lys Met Ala Lys Asn Trp Ser Ala Ala Gly Asn Ala
50 55 60 Phe Cys Gln
Ala Ala Lys Leu His Met Gln Leu Gln Ser Lys His Asp 65
70 75 80 Ser Ala Thr Ser Phe Val Asp
Ala Gly Asn Ala Tyr Lys Lys Ala Asp 85
90 95 Pro Gln Glu Ala Ile Asn Cys Leu Asn Ala Ala
Ile Asp Ile Tyr Thr 100 105
110 Asp Met Gly Arg Phe Thr Ile Ala Ala Lys His His Ile Thr Ile
Ala 115 120 125 Glu
Ile Tyr Glu Thr Glu Leu Val Asp Ile Glu Lys Ala Ile Ala His 130
135 140 Tyr Glu Gln Ser Ala Asp
Tyr Tyr Lys Gly Glu Glu Ser Asn Ser Ser 145 150
155 160 Ala Asn Lys Cys Leu Leu Lys Val Ala Ala Tyr
Ala Ala Gln Leu Glu 165 170
175 Gln Tyr Gln Lys Ala Ile Glu Ile Tyr Glu Gln Val Gly Ala Asn Thr
180 185 190 Met Asp
Asn Pro Leu Leu Lys Tyr Ser Ala Lys Asp Tyr Phe Phe Lys 195
200 205 Ala Ala Leu Cys His Phe Ile
Val Asp Glu Leu Asn Ala Lys Leu Ala 210 215
220 Leu Glu Lys Tyr Glu Glu Met Phe Pro Ala Phe Thr
Asp Ser Arg Glu 225 230 235
240 Cys Lys Leu Leu Lys Lys Leu Leu Glu Ala His Glu Glu Gln Asn Ser
245 250 255 Glu Ala Tyr
Thr Glu Ala Val Lys Glu Phe Asp Ser Ile Ser Arg Leu 260
265 270 Asp Gln Trp Leu Thr Thr Met Leu
Leu Arg Ile Lys Lys Ser Ile Gln 275 280
285 Gly Asp Gly Glu Gly Asp Gly Asp Leu Lys 290
295 51504PRTMus musculus 51Met Arg Phe Ser Cys
Leu Ala Leu Leu Pro Gly Val Ala Leu Leu Leu 1 5
10 15 Ala Ser Ala Arg Leu Ala Ala Ala Ser Asp
Val Leu Glu Leu Thr Asp 20 25
30 Glu Asn Phe Glu Ser Arg Val Ser Asp Thr Gly Ser Ala Gly Leu
Met 35 40 45 Leu
Val Glu Phe Phe Ala Pro Trp Cys Gly His Cys Lys Arg Leu Ala 50
55 60 Pro Glu Tyr Glu Ala Ala
Ala Thr Arg Leu Lys Ile Val Pro Leu Ala 65 70
75 80 Lys Val Asp Cys Thr Ala Asn Thr Asn Thr Cys
Asn Lys Tyr Gly Val 85 90
95 Ser Gly Tyr Pro Thr Leu Lys Ile Phe Arg Ala Gly Glu Glu Ala Gly
100 105 110 Ala Tyr
Asp Gly Pro Arg Thr Ala Asp Gly Ile Val Ser His Leu Lys 115
120 125 Lys Gln Ala Gly Pro Ala Ser
Val Pro Leu Arg Thr Glu Glu Glu Phe 130 135
140 Lys Lys Phe Ile Ser Asp Lys Asp Ala Ser Val Val
Gly Phe Phe Arg 145 150 155
160 Asp Leu Phe Ser Asp Gly His Ser Glu Phe Leu Lys Ala Ala Ser Asn
165 170 175 Leu Arg Asp
Asn Tyr Arg Phe Ala His Thr Asn Ile Glu Ser Leu Val 180
185 190 Lys Glu Tyr Asp Asp Asn Gly Glu
Gly Ile Thr Ile Phe Arg Pro Leu 195 200
205 His Leu Ala Asn Lys Phe Glu Asp Lys Thr Val Ala Tyr
Thr Glu Lys 210 215 220
Lys Met Thr Ser Ala Lys Ile Lys Lys Phe Ile Gln Asp Ser Ile Phe 225
230 235 240 Gly Leu Cys Pro
His Met Thr Glu Asp Asn Lys Asp Leu Ile Gln Gly 245
250 255 Lys Asp Leu Leu Thr Ala Tyr Tyr Asp
Val Asp Tyr Glu Lys Asn Ala 260 265
270 Lys Gly Ser Asn Tyr Trp Arg Asn Arg Val Met Met Val Ala
Lys Lys 275 280 285
Phe Leu Asp Ala Gly His Lys Leu Asn Phe Ala Val Ala Ser Arg Lys 290
295 300 Thr Phe Ser His Glu
Leu Ser Asp Phe Ser Leu Glu Ser Thr Thr Gly 305 310
315 320 Glu Val Pro Val Val Ala Ile Arg Thr Ala
Lys Gly Glu Lys Phe Val 325 330
335 Met Gln Glu Glu Phe Ser Arg Asp Gly Lys Ala Leu Glu Gln Phe
Leu 340 345 350 Gln
Glu Tyr Phe Asp Gly Asn Leu Lys Arg Tyr Leu Lys Ser Glu Pro 355
360 365 Ile Pro Glu Ser Asn Glu
Gly Pro Val Lys Val Val Val Ala Glu Asn 370 375
380 Phe Asp Asp Ile Val Asn Glu Glu Asp Lys Asp
Val Leu Ile Glu Phe 385 390 395
400 Tyr Ala Pro Trp Cys Gly His Cys Lys Asn Leu Glu Pro Lys Tyr Lys
405 410 415 Glu Leu
Gly Glu Lys Leu Ser Lys Asp Pro Asn Ile Val Ile Ala Lys 420
425 430 Met Asp Ala Thr Ala Asn Asp
Val Pro Ser Pro Tyr Glu Val Lys Gly 435 440
445 Phe Pro Thr Ile Tyr Phe Ser Pro Ala Asn Lys Lys
Leu Thr Pro Lys 450 455 460
Lys Tyr Glu Gly Gly Arg Glu Leu Asn Asp Phe Ile Ser Tyr Leu Gln 465
470 475 480 Arg Glu Ala
Thr Asn Pro Pro Ile Ile Gln Glu Glu Lys Pro Lys Lys 485
490 495 Lys Lys Lys Ala Gln Glu Asp Leu
500 52157PRTRattus norvegicus 52Met Val Asp
Ala Asp Glu Ile Lys Arg Leu Gly Lys Arg Phe Lys Lys 1 5
10 15 Leu Asp Leu Asp Asn Ser Gly Ser
Leu Ser Val Glu Glu Phe Met Ser 20 25
30 Leu Pro Glu Leu Gln Gln Asn Pro Leu Val Gln Arg Val
Ile Asp Ile 35 40 45
Phe Asp Thr Asp Gly Asn Gly Glu Val Asp Phe Lys Glu Phe Ile Glu 50
55 60 Gly Val Ser Gln
Phe Ser Val Lys Gly Asp Lys Glu Gln Lys Leu Arg 65 70
75 80 Phe Ala Phe Arg Ile Tyr Asp Met Asp
Lys Asp Gly Tyr Ile Ser Asn 85 90
95 Gly Glu Leu Phe Gln Val Leu Lys Met Met Val Gly Asn Asn
Leu Lys 100 105 110
Asp Thr Gln Leu Gln Gln Ile Val Asp Lys Thr Ile Ile Asn Ala Asp
115 120 125 Lys Asp Gly Asp
Gly Arg Ile Ser Phe Glu Glu Phe Cys Ala Val Val 130
135 140 Gly Gly Leu Asp Ile His Lys Lys
Met Val Val Asp Val 145 150 155
53261PRTMus musculus 53Met Ala Glu Ser His Leu Gln Ser Ser Leu Ile Thr
Ala Ser Gln Phe 1 5 10
15 Phe Glu Ile Trp Leu His Phe Asp Ala Asp Gly Ser Gly Tyr Leu Glu
20 25 30 Gly Lys Glu
Leu Gln Asn Leu Ile Gln Glu Leu Leu Gln Ala Arg Lys 35
40 45 Lys Ala Gly Leu Glu Leu Ser Pro
Glu Met Lys Ser Phe Val Asp Gln 50 55
60 Tyr Gly Gln Arg Asp Asp Gly Lys Ile Gly Ile Val Glu
Leu Ala His 65 70 75
80 Val Leu Pro Thr Glu Glu Asn Phe Leu Leu Leu Phe Arg Cys Gln Gln
85 90 95 Leu Lys Ser Cys
Glu Glu Phe Met Lys Thr Trp Arg Lys Tyr Asp Thr 100
105 110 Asp His Ser Gly Phe Ile Glu Thr Glu
Glu Leu Lys Asn Phe Leu Lys 115 120
125 Asp Leu Leu Glu Lys Ala Asn Lys Thr Val Asp Asp Thr Lys
Leu Ala 130 135 140
Glu Tyr Thr Asp Leu Met Leu Lys Leu Phe Asp Ser Asn Asn Asp Gly 145
150 155 160 Lys Leu Glu Leu Thr
Glu Met Ala Arg Leu Leu Pro Val Gln Glu Asn 165
170 175 Phe Leu Leu Lys Phe Gln Gly Ile Lys Met
Cys Gly Lys Glu Phe Asn 180 185
190 Lys Ala Phe Glu Leu Tyr Asp Gln Asp Gly Asn Gly Tyr Ile Asp
Glu 195 200 205 Asn
Glu Leu Asp Ala Leu Leu Lys Asp Leu Cys Glu Lys Asn Lys Gln 210
215 220 Glu Leu Asp Ile Asn Asn
Ile Thr Thr Tyr Lys Lys Asn Ile Met Ala 225 230
235 240 Leu Ser Asp Gly Gly Lys Leu Tyr Arg Thr Asp
Leu Ala Leu Ile Leu 245 250
255 Ser Ala Gly Asp Asn 260 54190PRTMus musculus
54Lys Ile Glu Met Ala Glu Leu Ala Gln Ile Leu Pro Thr Glu Glu Asn 1
5 10 15 Phe Leu Leu Cys
Phe Arg Gln His Val Gly Ser Ser Ala Glu Phe Met 20
25 30 Glu Ala Trp Arg Lys Tyr Asp Thr Asp
Arg Ser Gly Tyr Ile Glu Ala 35 40
45 Asn Glu Leu Lys Gly Phe Leu Ser Asp Leu Leu Lys Lys Ala
Asn Arg 50 55 60
Pro Tyr Asp Glu Pro Lys Leu Gln Glu Tyr Thr Gln Thr Ile Leu Arg 65
70 75 80 Met Phe Asp Leu Asn
Gly Asp Gly Lys Leu Gly Leu Ser Glu Met Ser 85
90 95 Arg Leu Leu Pro Val Gln Glu Asn Phe Leu
Leu Lys Phe Gln Gly Met 100 105
110 Lys Leu Thr Ser Glu Glu Phe Asn Ala Ile Phe Thr Phe Tyr Asp
Lys 115 120 125 Asp
Gly Ser Gly Tyr Ile Asp Glu Asn Glu Leu Asp Ala Leu Leu Lys 130
135 140 Asp Leu Tyr Glu Lys Asn
Lys Lys Glu Met Asn Ile Gln Gln Leu Thr 145 150
155 160 Thr Tyr Arg Lys Ser Val Met Ser Leu Ala Glu
Ala Gly Lys Leu Tyr 165 170
175 Arg Lys Asp Leu Glu Ile Val Leu Cys Ser Glu Pro Pro Val
180 185 190 55191PRTMus musculus
55Met Gly Lys Gln Asn Ser Lys Leu Ala Pro Glu Val Met Glu Asp Leu 1
5 10 15 Val Lys Ser Thr
Glu Phe Asn Glu His Glu Leu Lys Gln Trp Tyr Lys 20
25 30 Gly Phe Leu Lys Asp Cys Pro Ser Gly
Arg Leu Asn Leu Glu Glu Phe 35 40
45 Gln Gln Leu Tyr Val Lys Phe Phe Pro Tyr Gly Asp Ala Ser
Lys Phe 50 55 60
Ala Gln His Ala Phe Arg Thr Phe Asp Lys Asn Gly Asp Gly Thr Ile 65
70 75 80 Asp Phe Arg Glu Phe
Ile Cys Ala Leu Ser Ile Thr Ser Arg Gly Ser 85
90 95 Phe Glu Gln Lys Leu Asn Trp Ala Phe Asn
Met Tyr Asp Leu Asp Gly 100 105
110 Asp Gly Lys Ile Thr Arg Val Glu Met Leu Glu Ile Ile Glu Ala
Ile 115 120 125 Tyr
Lys Met Val Gly Thr Val Ile Met Met Lys Met Asn Glu Asp Gly 130
135 140 Leu Thr Pro Glu Gln Arg
Val Asp Lys Ile Phe Ser Lys Met Asp Lys 145 150
155 160 Asn Lys Asp Asp Gln Ile Thr Leu Asp Glu Phe
Lys Glu Ala Ala Lys 165 170
175 Ser Asp Pro Ser Ile Val Leu Leu Leu Gln Cys Asp Ile Gln Lys
180 185 190 56253PRTMus
musculus 56Met Ala Leu Ser Met Pro Leu Asn Gly Leu Lys Glu Glu Asp Lys
Glu 1 5 10 15 Pro
Leu Ile Glu Leu Phe Val Lys Ala Gly Ser Asp Gly Glu Ser Ile
20 25 30 Gly Asn Cys Pro Phe
Ser Gln Arg Leu Phe Met Ile Leu Trp Leu Lys 35
40 45 Gly Val Val Phe Ser Val Thr Thr Val
Asp Leu Lys Arg Lys Pro Ala 50 55
60 Asp Leu Gln Asn Leu Ala Pro Gly Thr His Pro Pro Phe
Ile Thr Phe 65 70 75
80 Asn Ser Glu Val Lys Thr Asp Val Asn Lys Ile Glu Glu Phe Leu Glu
85 90 95 Glu Val Leu Cys
Pro Pro Lys Tyr Leu Lys Leu Ser Pro Lys His Pro 100
105 110 Glu Ser Asn Thr Ala Gly Met Asp Ile
Phe Ala Lys Phe Ser Ala Tyr 115 120
125 Ile Lys Asn Ser Arg Pro Glu Ala Asn Glu Ala Leu Glu Arg
Gly Leu 130 135 140
Leu Lys Thr Leu Gln Lys Leu Asp Glu Tyr Leu Asn Ser Pro Leu Pro 145
150 155 160 Asp Glu Ile Asp Glu
Asn Ser Met Glu Asp Ile Lys Phe Ser Thr Arg 165
170 175 Arg Phe Leu Asp Gly Asp Glu Met Thr Leu
Ala Asp Cys Asn Leu Leu 180 185
190 Pro Lys Leu His Ile Val Lys Val Val Ala Lys Lys Tyr Arg Asn
Phe 195 200 205 Asp
Ile Pro Lys Gly Met Thr Gly Ile Trp Arg Tyr Leu Thr Asn Ala 210
215 220 Tyr Ser Arg Asp Glu Phe
Thr Asn Thr Cys Pro Ser Asp Lys Glu Val 225 230
235 240 Glu Ile Ala Tyr Ser Asp Val Ala Lys Arg Leu
Thr Lys 245 250 57187PRTMus
musculus 57 Met Ala Ala Asp Ile Ser Gln Trp Ala Gly Pro Leu Cys Leu Gln
Glu 1 5 10 15 Val
Asp Glu Pro Pro Gln His Ala Leu Arg Val Asp Tyr Ala Gly Val
20 25 30 Thr Val Asp Glu Leu
Gly Lys Val Leu Thr Pro Thr Gln Val Met Asn 35
40 45 Arg Pro Ser Ser Ile Ser Trp Asp Gly
Leu Asp Pro Gly Lys Leu Tyr 50 55
60 Thr Leu Val Leu Thr Asp Pro Asp Ala Pro Ser Arg Lys
Asp Pro Lys 65 70 75
80 Phe Arg Glu Trp His His Phe Leu Val Val Asn Met Lys Gly Asn Asp
85 90 95 Ile Ser Ser Gly
Thr Val Leu Ser Asp Tyr Val Gly Ser Gly Pro Pro 100
105 110 Ser Gly Thr Gly Leu His Arg Tyr Val
Trp Leu Val Tyr Glu Gln Glu 115 120
125 Gln Pro Leu Ser Cys Asp Glu Pro Ile Leu Ser Asn Lys Ser
Gly Asp 130 135 140
Asn Arg Gly Lys Phe Lys Val Glu Thr Phe Arg Lys Lys Tyr Asn Leu 145
150 155 160 Gly Ala Pro Ala Ala
Gly Thr Cys Tyr Gln Ala Lys Trp Asp Asp Tyr 165
170 175 Val Pro Lys Leu Tyr Lys Gln Leu Ser Gly
Lys 180 185 58256PRTMus musculus
58Gly Arg Phe Leu Gln Pro Glu Glu Tyr Pro Val Met Asp Lys Asn Glu 1
5 10 15 Leu Val Gln Lys
Ala Lys Leu Ala Glu Gln Ala Glu Arg Tyr Asp Asp 20
25 30 Met Ala Ala Cys Met Lys Ser Val Thr
Glu Gln Gly Ala Glu Leu Ser 35 40
45 Asn Glu Glu Arg Asn Leu Leu Ser Val Ala Tyr Lys Asn Val
Val Gly 50 55 60
Ala Arg Arg Ser Ser Trp Arg Val Val Ser Ser Ile Glu Gln Lys Thr 65
70 75 80 Glu Gly Ala Glu Lys
Lys Gln Gln Met Ala Arg Glu Tyr Arg Glu Lys 85
90 95 Ile Glu Thr Glu Leu Arg Asp Ile Cys Asn
Asp Val Leu Ser Leu Leu 100 105
110 Glu Lys Phe Leu Ile Pro Asn Ala Ser Gln Pro Glu Ser Lys Val
Phe 115 120 125 Tyr
Leu Lys Met Lys Gly Asp Tyr Tyr Arg Tyr Leu Ala Glu Val Ala 130
135 140 Ala Gly Asp Asp Lys Lys
Gly Ile Val Asp Gln Ser Gln Gln Ala Tyr 145 150
155 160 Gln Glu Ala Phe Glu Ile Ser Lys Lys Glu Met
Gln Pro Thr His Pro 165 170
175 Ile Arg Leu Gly Leu Ala Leu Asn Phe Ser Val Phe Tyr Tyr Glu Ile
180 185 190 Leu Asn
Ser Pro Glu Lys Ala Cys Ser Leu Ala Lys Thr Ala Phe Asp 195
200 205 Glu Ala Ile Ala Glu Leu Asp
Thr Leu Ser Glu Glu Ser Tyr Lys Asp 210 215
220 Ser Thr Leu Ile Met Gln Leu Leu Arg Asp Asn Leu
Thr Leu Trp Thr 225 230 235
240 Ser Asp Thr Gln Gly Asp Glu Ala Glu Ala Gly Glu Gly Gly Glu Asn
245 250 255 59175PRTMus
musculus 59 Met Ile Arg Glu Tyr Arg Gln Met Val Glu Thr Glu Leu Lys Leu
Ile 1 5 10 15 Cys
Cys Asp Ile Leu Asp Val Leu Asp Lys His Leu Ile Pro Ala Ala
20 25 30 Asn Thr Gly Glu Ser
Lys Val Phe Tyr Tyr Lys Met Lys Gly Asp Tyr 35
40 45 His Arg Tyr Leu Ala Glu Phe Ala Thr
Gly Asn Asp Arg Lys Glu Ala 50 55
60 Ala Glu Asn Ser Leu Val Ala Tyr Lys Ala Ala Ser Asp
Ile Ala Met 65 70 75
80 Thr Glu Leu Pro Pro Thr His Pro Ile Arg Leu Gly Leu Ala Leu Asn
85 90 95 Phe Ser Val Phe
Tyr Tyr Glu Ile Leu Asn Ser Pro Asp Arg Ala Cys 100
105 110 Arg Leu Ala Lys Ala Ala Phe Asp Asp
Ala Ile Ala Glu Leu Asp Thr 115 120
125 Leu Ser Glu Glu Ser Tyr Lys Asp Ser Thr Leu Ile Met Gln
Leu Leu 130 135 140
Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Met Gln Gly Asp Gly Glu 145
150 155 160 Glu Gln Asn Lys Glu
Ala Leu Gln Asp Val Glu Asp Glu Asn Gln 165
170 175 60199PRTMus musculus 60 Met Ser Ser Gly Asn Ala
Lys Ile Gly Tyr Pro Ala Pro Asn Phe Lys 1 5
10 15 Ala Thr Ala Val Met Pro Asp Gly Gln Phe Lys
Asp Ile Ser Leu Ser 20 25
30 Glu Tyr Lys Gly Lys Tyr Val Val Phe Phe Phe Tyr Pro Leu Asp
Phe 35 40 45 Thr
Phe Val Cys Pro Thr Glu Ile Ile Ala Phe Ser Asp Arg Ala Asp 50
55 60 Glu Phe Lys Lys Leu Asn
Cys Gln Val Ile Gly Ala Ser Val Asp Ser 65 70
75 80 His Phe Cys His Leu Ala Trp Ile Asn Thr Pro
Lys Lys Gln Gly Gly 85 90
95 Leu Gly Pro Met Asn Ile Pro Leu Ile Ser Asp Pro Lys Arg Thr Ile
100 105 110 Ala Gln
Asp Tyr Gly Val Leu Lys Ala Asp Glu Gly Ile Ser Phe Arg 115
120 125 Gly Leu Phe Ile Ile Asp Asp
Lys Gly Ile Leu Arg Gln Ile Thr Ile 130 135
140 Asn Asp Leu Pro Val Gly Arg Ser Val Asp Glu Ile
Ile Arg Leu Val 145 150 155
160 Gln Ala Phe Gln Phe Thr Asp Lys His Gly Glu Val Cys Pro Ala Gly
165 170 175 Trp Lys Pro
Gly Ser Asp Thr Ile Lys Pro Asp Val Asn Lys Ser Lys 180
185 190 Glu Tyr Phe Ser Lys Gln Lys
195 61257PRTMus musculus 61Met Ala Ala Ala Ala Gly
Arg Leu Leu Trp Ser Ser Val Ala Arg His 1 5
10 15 Ala Ser Ala Ile Ser Arg Ser Ile Ser Ala Ser
Thr Val Leu Arg Pro 20 25
30 Val Ala Ser Arg Arg Thr Cys Leu Thr Asp Ile Leu Trp Ser Ala
Ser 35 40 45 Ala
Gln Gly Lys Ser Ala Phe Ser Thr Ser Ser Ser Phe His Thr Pro 50
55 60 Ala Val Thr Gln His Ala
Pro Tyr Phe Lys Gly Thr Ala Val Val Asn 65 70
75 80 Gly Glu Phe Lys Glu Leu Ser Leu Asp Asp Phe
Lys Gly Lys Tyr Leu 85 90
95 Val Leu Phe Phe Tyr Pro Leu Asp Phe Thr Phe Val Cys Pro Thr Glu
100 105 110 Ile Val
Ala Phe Ser Asp Lys Ala Asn Glu Phe His Asp Val Asn Cys 115
120 125 Glu Val Val Ala Val Ser Val
Asp Ser His Phe Ser His Leu Ala Trp 130 135
140 Ile Asn Thr Pro Arg Lys Asn Gly Gly Leu Gly His
Met Asn Ile Thr 145 150 155
160 Leu Leu Ser Asp Ile Thr Lys Gln Ile Ser Arg Asp Tyr Gly Val Leu
165 170 175 Leu Glu Ser
Ala Gly Ile Ala Leu Arg Gly Leu Phe Ile Ile Asp Pro 180
185 190 Asn Gly Val Val Lys His Leu Ser
Val Asn Asp Leu Pro Val Gly Arg 195 200
205 Ser Val Glu Glu Thr Leu Arg Leu Val Lys Ala Phe Gln
Phe Val Glu 210 215 220
Thr His Gly Glu Val Cys Pro Ala Asn Trp Thr Pro Glu Ser Pro Thr 225
230 235 240 Ile Lys Pro Ser
Pro Thr Ala Ser Lys Glu Tyr Phe Glu Lys Val His 245
250 255 Gln 62312PRTMus musculus 62Met Glu
Gly Glu Cys Arg Val Leu Ser Ile Gln Ser His Val Val Arg 1 5
10 15 Gly Tyr Val Gly Asn Arg Ala
Ala Met Phe Pro Leu Gln Val Leu Gly 20 25
30 Phe Glu Val Asp Ala Val Asn Ser Val Gln Phe Ser
Asn His Thr Gly 35 40 45
Tyr Ala His Trp Lys Gly Gln Val Leu Lys Ser Gln Glu Leu His Glu
50 55 60 Leu Tyr Glu
Gly Leu Lys Val Asn Asp Val Asn Lys Tyr Asp Tyr Val 65
70 75 80 Leu Thr Gly Tyr Thr Arg Asp
Lys Ser Phe Leu Ala Met Val Val Asp 85
90 95 Ile Val Arg Glu Leu Lys Gln Gln Asn Ser Arg
Leu Val Tyr Val Cys 100 105
110 Asp Pro Val Met Gly Asp Lys Trp Asn Gly Glu Gly Ser Met Tyr
Val 115 120 125 Pro
Gln Asp Leu Leu Pro Val Tyr Arg Asp Lys Val Val Pro Val Ala 130
135 140 Asp Ile Ile Thr Pro Asn
Gln Phe Glu Ala Glu Leu Leu Ser Gly Arg 145 150
155 160 Lys Ile His Ser Gln Glu Glu Ala Phe Glu Val
Met Asp Met Leu His 165 170
175 Cys Met Gly Pro Asp Thr Val Val Ile Thr Ser Ser Asp Leu Pro Ser
180 185 190 Ser Gln
Gly Ser Asp Tyr Leu Ile Ala Leu Gly Ser Gln Arg Met Arg 195
200 205 Lys Pro Asp Gly Ser Thr Val
Thr Gln Arg Ile Arg Met Glu Met Arg 210 215
220 Lys Val Glu Ala Val Phe Val Gly Thr Gly Asp Leu
Phe Ala Ala Met 225 230 235
240 Leu Leu Ala Trp Thr His Lys His Pro Asp Asn Leu Lys Val Ala Cys
245 250 255 Glu Lys Thr
Val Ser Ala Met Gln His Val Leu Gln Arg Thr Ile Arg 260
265 270 Cys Ala Lys Ala Glu Ala Gly Glu
Gly Gln Lys Pro Ser Pro Ala Gln 275 280
285 Leu Glu Leu Arg Met Val Gln Ser Lys Arg Asp Ile Glu
Asp Pro Glu 290 295 300
Ile Val Val Gln Ala Thr Val Leu 305 310
63354PRTMus musculus 63Met Gly Cys Thr Leu Ser Ala Glu Glu Arg Ala Ala
Leu Glu Arg Ser 1 5 10
15 Lys Ala Ile Glu Lys Asn Leu Lys Glu Asp Gly Ile Ser Ala Ala Lys
20 25 30 Asp Val Lys
Leu Leu Leu Leu Gly Ala Gly Glu Ser Gly Lys Ser Thr 35
40 45 Ile Val Lys Gln Met Lys Ile Ile
His Glu Asp Gly Phe Ser Gly Glu 50 55
60 Asp Val Lys Gln Tyr Lys Pro Val Val Tyr Ser Asn Thr
Ile Gln Ser 65 70 75
80 Leu Ala Ala Ile Val Arg Ala Met Asp Thr Leu Gly Val Glu Tyr Gly
85 90 95 Asp Lys Glu Arg
Lys Thr Asp Ser Lys Met Val Cys Asp Val Val Ser 100
105 110 Arg Met Glu Asp Thr Glu Pro Phe Ser
Ala Glu Leu Leu Ser Ala Met 115 120
125 Met Arg Leu Trp Gly Asp Ser Gly Ile Gln Glu Cys Phe Asn
Arg Ser 130 135 140
Arg Glu Tyr Gln Leu Asn Asp Ser Ala Lys Tyr Tyr Leu Asp Ser Leu 145
150 155 160 Asp Arg Ile Gly Ala
Gly Asp Tyr Gln Pro Thr Glu Gln Asp Ile Leu 165
170 175 Arg Thr Arg Val Lys Thr Thr Gly Ile Val
Glu Thr His Phe Thr Phe 180 185
190 Lys Asn Leu His Phe Arg Leu Phe Asp Val Gly Gly Gln Arg Ser
Glu 195 200 205 Arg
Lys Lys Trp Ile His Cys Phe Glu Asp Val Thr Ala Ile Ile Phe 210
215 220 Cys Val Ala Leu Ser Gly
Tyr Asp Gln Val Leu His Glu Asp Glu Thr 225 230
235 240 Thr Asn Arg Met His Glu Ser Leu Lys Leu Phe
Asp Ser Ile Cys Asn 245 250
255 Asn Lys Trp Phe Thr Asp Thr Ser Ile Ile Leu Phe Leu Asn Lys Lys
260 265 270 Asp Ile
Phe Glu Glu Lys Ile Lys Lys Ser Pro Leu Thr Ile Cys Phe 275
280 285 Pro Glu Tyr Thr Gly Pro Ser
Ala Phe Thr Glu Ala Val Ala His Ile 290 295
300 Gln Gly Gln Tyr Glu Ser Lys Asn Lys Ser Ala His
Lys Glu Val Tyr 305 310 315
320 Ser His Val Thr Cys Ala Thr Asp Thr Asn Asn Ile Gln Phe Val Phe
325 330 335 Asp Ala Val
Thr Asp Val Ile Ile Ala Lys Asn Leu Arg Gly Cys Gly 340
345 350 Leu Tyr 642199DNAHomo sapiens
64gggacaaact tttcccaaac ccgatccgag cccttggacc aaactcgcct gcgccgagag
60ccgtccgcgt agagcgctcc gtctccggcg agatgtccga gcgcaaagaa ggcagaggca
120aagggaaggg caagaagaag gagcgaggct ccggcaagaa gccggagtcc gcggcgggca
180gccagagccc agccttgcct ccccaattga aagagatgaa aagccaggaa tcggctgcag
240gttccaaact agtccttcgg tgtgaaacca gttctgaata ctcctctctc agattcaagt
300ggttcaagaa tgggaatgaa ttgaatcgaa aaaacaaacc acaaaatatc aagatacaaa
360aaaagccagg gaagtcagaa cttcgcatta acaaagcatc actggctgat tctggagagt
420atatgtgcaa agtgatcagc aaattaggaa atgacagtgc ctctgccaat atcaccatcg
480tggaatcaaa cgagatcatc actggtatgc cagcctcaac tgaaggagca tatgtgtctt
540cagagtctcc cattagaata tcagtatcca cagaaggagc aaatacttct tcatctacat
600ctacatccac cactgggaca agccatcttg taaaatgtgc ggagaaggag aaaactttct
660gtgtgaatgg aggggagtgc ttcatggtga aagacctttc aaacccctcg agatacttgt
720gcaagtgccc aaatgagttt actggtgatc gctgccaaaa ctacgtaatg gccagcttct
780acaagcatct tgggattgaa tttatggagg cggaggagct gtaccagaag agagtgctga
840ccataaccgg catctgcatc gccctccttg tggtcggcat catgtgtgtg gtggcctact
900gcaaaaccaa gaaacagcgg aaaaagctgc atgaccgtct tcggcagagc cttcggtctg
960aacgaaacaa tatgatgaac attgccaatg ggcctcacca tcctaaccca ccccccgaga
1020atgtccagct ggtgaatcaa tacgtatcta aaaacgtcat ctccagtgag catattgttg
1080agagagaagc agagacatcc ttttccacca gtcactatac ttccacagcc catcactcca
1140ctactgtcac ccagactcct agccacagct ggagcaacgg acacactgaa agcatccttt
1200ccgaaagcca ctctgtaatc gtgatgtcat ccgtagaaaa cagtaggcac agcagcccaa
1260ctgggggccc aagaggacgt cttaatggca caggaggccc tcgtgaatgt aacagcttcc
1320tcaggcatgc cagagaaacc cctgattcct accgagactc tcctcatagt gaaaggtatg
1380tgtcagccat gaccaccccg gctcgtatgt cacctgtaga tttccacacg ccaagctccc
1440ccaaatcgcc cccttcggaa atgtctccac ccgtgtccag catgacggtg tccatgcctt
1500ccatggcggt cagccccttc atggaagaag agagacctct acttctcgtg acaccaccaa
1560ggctgcggga gaagaagttt gaccatcacc ctcagcagtt cagctccttc caccacaacc
1620ccgcgcatga cagtaacagc ctccctgcta gccccttgag gatagtggag gatgaggagt
1680atgaaacgac ccaagagtac gagccagccc aagagcctgt taagaaactc gccaatagcc
1740ggcgggccaa aagaaccaag cccaatggcc acattgctaa cagattggaa gtggacagca
1800acacaagctc ccagagcagt aactcagaga gtgaaacaga agatgaaaga gtaggtgaag
1860atacgccttt cctgggcata cagaaccccc tggcagccag tcttgaggca acacctgcct
1920tccgcctggc tgacagcagg actaacccag caggccgctt ctcgacacag gaagaaatcc
1980aggccaggct gtctagtgta attgctaacc aagaccctat tgctgtataa aacctaaata
2040aacacataga ttcacctgta aaactttatt ttatataata aagtattcca ccttaaatta
2100aacaatttat tttattttag cagttctgca aatagaaaac aggaaaaaaa cttttataaa
2160ttaaatatat gtatgtaaaa atgaaaaaaa aaaaaaaaa
219965299PRTMus musculus 65Met Glu Gly Lys Ala Glu Gln Gln Gly Ala Gly
Leu Thr Met Ala Glu 1 5 10
15 Gly Gly Glu Lys Glu Glu Phe Cys Phe Thr Ala Ile Tyr Ile Ser Gly
20 25 30 Gln Trp
Arg Glu Pro Cys Val Cys Thr Asp Leu Gln Arg Leu Glu Pro 35
40 45 Gly Thr Met Ala Pro Thr Arg
Lys Phe Phe Val Gly Gly Asn Trp Lys 50 55
60 Met Asn Gly Arg Lys Lys Cys Leu Gly Glu Leu Ile
Cys Thr Leu Asn 65 70 75
80 Ala Ala Asn Val Pro Ala Gly Thr Glu Val Val Cys Ala Pro Pro Thr
85 90 95 Ala Tyr Ile
Asp Phe Ala Arg Gln Lys Leu Asp Pro Lys Ile Ala Val 100
105 110 Ala Ala Gln Asn Cys Tyr Lys Val
Thr Asn Gly Ala Phe Thr Gly Glu 115 120
125 Ile Ser Pro Gly Met Ile Lys Asp Leu Gly Ala Thr Trp
Val Val Leu 130 135 140
Gly His Ser Glu Arg Arg His Val Phe Gly Glu Ser Asp Glu Leu Ile 145
150 155 160 Gly Gln Lys Val
Ser His Ala Leu Ala Glu Gly Leu Gly Val Ile Ala 165
170 175 Cys Ile Gly Glu Lys Leu Asp Glu Arg
Glu Ala Gly Ile Thr Glu Lys 180 185
190 Val Val Phe Glu Gln Thr Lys Val Ile Ala Asp Asn Val Lys
Asp Trp 195 200 205
Ser Lys Val Val Leu Ala Tyr Glu Pro Val Trp Ala Ile Gly Thr Gly 210
215 220 Lys Thr Ala Thr Pro
Gln Gln Ala Gln Glu Val His Glu Lys Leu Arg 225 230
235 240 Gly Trp Leu Lys Ser Asn Val Asn Asp Gly
Val Ala Gln Ser Thr Arg 245 250
255 Ile Ile Tyr Gly Gly Ser Val Thr Gly Ala Thr Cys Lys Glu Leu
Ala 260 265 270 Ser
Gln Pro Asp Val Asp Gly Phe Leu Val Gly Gly Ala Ser Leu Lys 275
280 285 Pro Glu Phe Val Asp Ile
Ile Asn Ala Lys Gln 290 295
66642PRTMus musculus 66Met Trp Arg Val Cys Ala Arg Arg Ala Arg Ser Ala
Val Pro Arg Asp 1 5 10
15 Gly Phe Arg Ala Arg Trp Ala Ala Leu Lys Glu Gly Pro Gly Ala Pro
20 25 30 Cys Gly Ser
Pro Arg Ile Gly Pro Ala Ala Val Arg Cys Gly Ser Gly 35
40 45 Ile Pro Arg Tyr Gly Val Arg Ser
Leu Cys Gly Trp Ser Ser Gly Ser 50 55
60 Gly Thr Val Pro Arg Asn Arg Leu Leu Arg Gln Leu Leu
Gly Ser Pro 65 70 75
80 Ser Arg Arg Ser Tyr Ser Leu Pro Pro His Gln Lys Val Pro Leu Pro
85 90 95 Ser Leu Ser Pro
Thr Met Gln Ala Gly Thr Ile Ala Arg Trp Glu Lys 100
105 110 Lys Glu Gly Glu Lys Ile Ser Glu Gly
Asp Leu Ile Ala Glu Val Glu 115 120
125 Thr Asp Lys Ala Thr Val Gly Phe Glu Ser Leu Glu Glu Cys
Tyr Met 130 135 140
Ala Lys Ile Leu Val Pro Glu Gly Thr Arg Asp Val Pro Val Gly Ser 145
150 155 160 Ile Ile Cys Ile Thr
Val Glu Lys Pro Gln Asp Ile Glu Ala Phe Lys 165
170 175 Asn Tyr Thr Leu Asp Leu Ala Ala Ala Ala
Ala Pro Gln Ala Ala Pro 180 185
190 Ala Ala Ala Pro Ala Pro Ala Ala Ala Pro Ala Ala Pro Ser Ala
Ser 195 200 205 Ala
Pro Gly Ser Ser Tyr Pro Thr His Met Gln Ile Val Leu Pro Ala 210
215 220 Leu Ser Pro Thr Met Thr
Met Gly Thr Val Gln Arg Trp Glu Lys Lys 225 230
235 240 Val Gly Glu Lys Leu Ser Glu Gly Asp Leu Leu
Ala Glu Ile Glu Thr 245 250
255 Asp Lys Ala Thr Ile Gly Phe Glu Val Gln Glu Glu Gly Tyr Leu Ala
260 265 270 Lys Ile
Leu Val Pro Glu Gly Thr Arg Asp Val Pro Leu Gly Ala Pro 275
280 285 Leu Cys Ile Ile Val Glu Lys
Gln Glu Asp Ile Ala Ala Phe Ala Asp 290 295
300 Tyr Arg Pro Thr Glu Val Thr Ser Leu Lys Pro Gln
Ala Ala Pro Pro 305 310 315
320 Ala Pro Pro Pro Val Ala Ala Val Pro Pro Thr Pro Gln Pro Val Ala
325 330 335 Pro Thr Pro
Ser Ala Ala Pro Ala Gly Pro Lys Gly Arg Val Phe Val 340
345 350 Ser Pro Leu Ala Lys Lys Leu Ala
Ala Glu Lys Gly Ile Asp Leu Thr 355 360
365 Gln Val Lys Gly Thr Gly Pro Glu Gly Arg Ile Ile Lys
Lys Asp Ile 370 375 380
Asp Ser Phe Val Pro Ser Lys Ala Ala Pro Ala Ala Ala Ala Ala Met 385
390 395 400 Ala Pro Pro Gly
Pro Arg Val Ala Pro Ala Pro Ala Gly Val Phe Thr 405
410 415 Asp Ile Pro Ile Ser Asn Ile Arg Arg
Val Ile Ala Gln Arg Leu Met 420 425
430 Gln Ser Lys Gln Thr Ile Pro His Tyr Tyr Leu Ser Val Asp
Val Asn 435 440 445
Met Gly Glu Val Leu Leu Val Arg Lys Glu Leu Asn Lys Met Leu Glu 450
455 460 Gly Lys Gly Lys Ile
Ser Val Asn Asp Phe Ile Ile Lys Ala Ser Ala 465 470
475 480 Leu Ala Cys Leu Lys Val Pro Glu Ala Asn
Ser Ser Trp Met Asp Thr 485 490
495 Val Ile Arg Gln Asn His Val Val Asp Val Ser Val Ala Val Ser
Thr 500 505 510 Pro
Ala Gly Leu Ile Thr Pro Ile Val Phe Asn Ala His Ile Lys Gly 515
520 525 Leu Glu Thr Ile Ala Ser
Asp Val Val Ser Leu Ala Ser Lys Ala Arg 530 535
540 Glu Gly Lys Leu Gln Pro His Glu Phe Gln Gly
Gly Thr Phe Thr Ile 545 550 555
560 Ser Asn Leu Gly Met Phe Gly Ile Lys Asn Phe Ser Ala Ile Ile Asn
565 570 575 Pro Pro
Gln Ala Cys Ile Leu Ala Ile Gly Ala Ser Glu Asp Lys Leu 580
585 590 Ile Pro Ala Asp Asn Glu Lys
Gly Phe Asp Val Ala Ser Val Met Ser 595 600
605 Val Thr Leu Ser Cys Asp His Arg Val Val Asp Gly
Ala Val Gly Ala 610 615 620
Gln Trp Leu Ala Glu Phe Lys Lys Tyr Leu Glu Lys Pro Ile Thr Met 625
630 635 640 Leu Leu
67727PRTMus musculus 67Met Leu Arg Ile Pro Ile Lys Arg Ala Leu Ile Gly
Leu Ser Asn Ser 1 5 10
15 Pro Lys Gly Tyr Val Arg Thr Thr Gly Thr Ala Ala Ser Asn Leu Ile
20 25 30 Glu Val Phe
Val Asp Gly Gln Ser Val Met Val Glu Pro Gly Thr Thr 35
40 45 Val Leu Gln Ala Cys Glu Lys Val
Gly Met Gln Ile Pro Arg Phe Cys 50 55
60 Tyr His Glu Arg Leu Ser Val Ala Gly Asn Cys Arg Met
Cys Leu Val 65 70 75
80 Glu Ile Glu Lys Ala Pro Lys Val Val Ala Ala Cys Ala Met Pro Val
85 90 95 Met Lys Gly Trp
Asn Ile Leu Thr Asn Ser Glu Lys Ser Lys Lys Ala 100
105 110 Arg Glu Gly Val Met Glu Phe Leu Leu
Ala Asn His Pro Leu Asp Cys 115 120
125 Pro Ile Cys Asp Gln Gly Gly Glu Cys Asp Leu Gln Asp Gln
Ser Met 130 135 140
Met Phe Gly Ser Asp Arg Ser Arg Phe Leu Glu Gly Lys Arg Ala Val 145
150 155 160 Glu Asp Lys Asn Ile
Gly Pro Leu Val Lys Thr Ile Met Thr Arg Cys 165
170 175 Ile Gln Cys Thr Arg Cys Ile Arg Phe Ala
Ser Glu Ile Ala Gly Val 180 185
190 Asp Asp Leu Gly Thr Thr Gly Arg Gly Asn Asp Met Gln Val Gly
Thr 195 200 205 Tyr
Ile Glu Lys Met Phe Met Ser Glu Leu Ser Gly Asn Val Ile Asp 210
215 220 Ile Cys Pro Val Gly Ala
Leu Thr Ser Lys Pro Tyr Ala Phe Thr Ala 225 230
235 240 Arg Pro Trp Glu Thr Arg Lys Thr Glu Ser Ile
Asp Val Met Asp Ala 245 250
255 Val Gly Ser Asn Ile Val Val Ser Thr Arg Thr Gly Glu Val Met Arg
260 265 270 Ile Leu
Pro Arg Met His Glu Asp Ile Asn Glu Glu Trp Ile Ser Asp 275
280 285 Lys Thr Arg Phe Ala Tyr Asp
Gly Leu Lys Arg Gln Arg Leu Thr Glu 290 295
300 Pro Met Val Arg Asn Glu Lys Gly Leu Leu Thr Tyr
Thr Ser Trp Glu 305 310 315
320 Asp Ala Leu Ser Arg Val Ala Gly Met Leu Gln Asn Phe Glu Gly Asn
325 330 335 Ala Val Ala
Ala Ile Ala Gly Gly Leu Val Asp Ala Glu Ala Leu Val 340
345 350 Ala Leu Lys Asp Leu Leu Asn Lys
Val Asp Ser Asp Asn Leu Cys Thr 355 360
365 Glu Glu Ile Phe Pro Thr Glu Gly Ala Gly Thr Asp Leu
Arg Ser Asn 370 375 380
Tyr Leu Leu Asn Thr Thr Ile Ala Gly Val Glu Glu Ala Asp Val Val 385
390 395 400 Leu Leu Val Gly
Thr Asn Pro Arg Phe Glu Ala Pro Leu Phe Asn Ala 405
410 415 Arg Ile Arg Lys Ser Trp Leu His Asn
Asp Leu Lys Val Ala Leu Ile 420 425
430 Gly Ser Pro Val Asp Leu Thr Tyr Arg Tyr Asp His Leu Gly
Asp Ser 435 440 445
Pro Lys Ile Leu Gln Asp Ile Ala Ser Gly Arg His Ser Phe Cys Glu 450
455 460 Val Leu Lys Asp Ala
Lys Lys Pro Met Val Val Leu Gly Ser Ser Ala 465 470
475 480 Leu Gln Arg Asp Asp Gly Ala Ala Ile Leu
Val Ala Val Ser Asn Met 485 490
495 Val Gln Lys Ile Arg Val Thr Thr Gly Val Ala Ala Glu Trp Lys
Val 500 505 510 Met
Asn Ile Leu His Arg Ile Ala Ser Gln Val Ala Ala Leu Asp Leu 515
520 525 Gly Tyr Lys Pro Gly Val
Glu Ala Ile Arg Lys Asn Pro Pro Lys Met 530 535
540 Leu Phe Leu Leu Gly Ala Asp Gly Gly Cys Ile
Thr Arg Gln Asp Leu 545 550 555
560 Pro Lys Asp Cys Phe Ile Val Tyr Gln Gly His His Gly Asp Val Gly
565 570 575 Ala Pro
Met Ala Asp Val Ile Leu Pro Gly Ala Ala Tyr Thr Glu Lys 580
585 590 Ser Ala Thr Tyr Val Asn Thr
Glu Gly Arg Ala Gln Gln Thr Lys Val 595 600
605 Ala Val Thr Pro Pro Gly Leu Ala Arg Glu Asp Trp
Lys Ile Ile Arg 610 615 620
Ala Leu Ser Glu Ile Ala Gly Ile Thr Leu Pro Tyr Asp Thr Leu Asp 625
630 635 640 Gln Val Arg
Asn Arg Leu Glu Glu Val Ser Pro Asn Leu Val Arg Tyr 645
650 655 Asp Asp Ile Glu Glu Thr Asn Tyr
Phe Gln Gln Ala Ser Glu Leu Ala 660 665
670 Lys Leu Val Asn Gln Glu Val Leu Ala Asp Pro Leu Val
Pro Pro Gln 675 680 685
Leu Thr Ile Lys Asp Phe Tyr Met Thr Asp Ser Ile Ser Arg Ala Ser 690
695 700 Gln Thr Met Ala
Lys Cys Val Lys Ala Val Thr Glu Gly Ala Gln Ala 705 710
715 720 Val Glu Glu Pro Ser Ile Cys
725 68364PRTHomo sapiens 68Met Pro Tyr Gln Tyr Pro Ala
Leu Thr Pro Glu Gln Lys Lys Glu Leu 1 5
10 15 Ser Asp Ile Ala His Arg Ile Val Ala Pro Gly
Lys Gly Ile Leu Ala 20 25
30 Ala Asp Glu Ser Thr Gly Ser Ile Ala Lys Arg Leu Gln Ser Ile
Gly 35 40 45 Thr
Glu Asn Thr Glu Glu Asn Arg Arg Phe Tyr Arg Gln Leu Leu Leu 50
55 60 Thr Ala Asp Asp Arg Val
Asn Pro Cys Ile Gly Gly Val Ile Leu Phe 65 70
75 80 His Glu Thr Leu Tyr Gln Lys Ala Asp Asp Gly
Arg Pro Phe Pro Gln 85 90
95 Val Ile Lys Ser Lys Gly Gly Val Val Gly Ile Lys Val Asp Lys Gly
100 105 110 Val Val
Pro Leu Ala Gly Thr Asn Gly Glu Thr Thr Thr Gln Gly Leu 115
120 125 Asp Gly Leu Ser Glu Arg Cys
Ala Gln Tyr Lys Lys Asp Gly Ala Asp 130 135
140 Phe Ala Lys Trp Arg Cys Val Leu Lys Ile Gly Glu
His Thr Pro Ser 145 150 155
160 Ala Leu Ala Ile Met Glu Asn Ala Asn Val Leu Ala Arg Tyr Ala Ser
165 170 175 Ile Cys Gln
Gln Asn Gly Ile Val Pro Ile Val Glu Pro Glu Ile Leu 180
185 190 Pro Asp Gly Asp His Asp Leu Lys
Arg Cys Gln Tyr Val Thr Glu Lys 195 200
205 Val Leu Ala Ala Val Tyr Lys Ala Leu Ser Asp His His
Ile Tyr Leu 210 215 220
Glu Gly Thr Leu Leu Lys Pro Asn Met Val Thr Pro Gly His Ala Cys 225
230 235 240 Thr Gln Lys Phe
Ser His Glu Glu Ile Ala Met Ala Thr Val Thr Ala 245
250 255 Leu Arg Arg Thr Val Pro Pro Ala Val
Thr Gly Ile Thr Phe Leu Ser 260 265
270 Gly Gly Gln Ser Glu Glu Glu Ala Ser Ile Asn Leu Asn Ala
Ile Asn 275 280 285
Lys Cys Pro Leu Leu Lys Pro Trp Ala Leu Thr Phe Ser Tyr Gly Arg 290
295 300 Ala Leu Gln Ala Ser
Ala Leu Lys Ala Trp Gly Gly Lys Lys Glu Asn 305 310
315 320 Leu Lys Ala Ala Gln Glu Glu Tyr Val Lys
Arg Ala Leu Ala Asn Ser 325 330
335 Leu Ala Cys Gln Gly Lys Tyr Thr Pro Ser Gly Gln Ala Gly Ala
Ala 340 345 350 Ala
Ser Glu Ser Leu Phe Val Ser Asn His Ala Tyr 355
360 69364PRTHomo sapiens 69Met Pro His Ser Tyr Pro Ala
Leu Ser Ala Glu Gln Lys Lys Glu Leu 1 5
10 15 Ser Asp Ile Ala Leu Arg Ile Val Ala Pro Gly
Lys Gly Ile Leu Ala 20 25
30 Ala Asp Glu Ser Val Gly Ser Met Ala Lys Arg Leu Ser Gln Ile
Gly 35 40 45 Val
Glu Asn Thr Glu Glu Asn Arg Arg Leu Tyr Arg Gln Val Leu Phe 50
55 60 Ser Ala Asp Asp Arg Val
Lys Lys Cys Ile Gly Gly Val Ile Phe Phe 65 70
75 80 His Glu Thr Leu Tyr Gln Lys Asp Asp Asn Gly
Val Pro Phe Val Arg 85 90
95 Thr Ile Gln Asp Lys Gly Ile Val Val Gly Ile Lys Val Asp Lys Gly
100 105 110 Val Val
Pro Leu Ala Gly Thr Asp Gly Glu Thr Thr Thr Gln Gly Leu 115
120 125 Asp Gly Leu Ser Glu Arg Cys
Ala Gln Tyr Lys Lys Asp Gly Ala Asp 130 135
140 Phe Ala Lys Trp Arg Cys Val Leu Lys Ile Ser Glu
Arg Thr Pro Ser 145 150 155
160 Ala Leu Ala Ile Leu Glu Asn Ala Asn Val Leu Ala Arg Tyr Ala Ser
165 170 175 Ile Cys Gln
Gln Asn Gly Ile Val Pro Ile Val Glu Pro Glu Ile Leu 180
185 190 Pro Asp Gly Asp His Asp Leu Lys
Arg Cys Gln Tyr Val Thr Glu Lys 195 200
205 Val Leu Ala Ala Val Tyr Lys Ala Leu Ser Asp His His
Val Tyr Leu 210 215 220
Glu Gly Thr Leu Leu Lys Pro Asn Met Val Thr Pro Gly His Ala Cys 225
230 235 240 Pro Ile Lys Tyr
Thr Pro Glu Glu Ile Ala Met Ala Thr Val Thr Ala 245
250 255 Leu Arg Arg Thr Val Pro Pro Ala Val
Pro Gly Val Thr Phe Leu Ser 260 265
270 Gly Gly Gln Ser Glu Glu Glu Ala Ser Phe Asn Leu Asn Ala
Ile Asn 275 280 285
Arg Cys Pro Leu Pro Arg Pro Trp Ala Leu Thr Phe Ser Tyr Gly Arg 290
295 300 Ala Leu Gln Ala Ser
Ala Leu Asn Ala Trp Arg Gly Gln Arg Asp Asn 305 310
315 320 Ala Gly Ala Ala Thr Glu Glu Phe Ile Lys
Arg Ala Glu Val Asn Gly 325 330
335 Leu Ala Ala Gln Gly Lys Tyr Glu Gly Ser Gly Glu Asp Gly Gly
Ala 340 345 350 Ala
Ala Gln Ser Leu Tyr Ile Ala Asn His Ala Tyr 355
360 70249PRTHomo sapiens 70Met Ala Pro Ser Arg Lys Phe
Phe Val Gly Gly Asn Trp Lys Met Asn 1 5
10 15 Gly Arg Lys Gln Ser Leu Gly Glu Leu Ile Gly
Thr Leu Asn Ala Ala 20 25
30 Lys Val Pro Ala Asp Thr Glu Val Val Cys Ala Pro Pro Thr Ala
Tyr 35 40 45 Ile
Asp Phe Ala Arg Gln Lys Leu Asp Pro Lys Ile Ala Val Ala Ala 50
55 60 Gln Asn Cys Tyr Lys Val
Thr Asn Gly Ala Phe Thr Gly Glu Ile Ser 65 70
75 80 Pro Gly Met Ile Lys Asp Cys Gly Ala Thr Trp
Val Val Leu Gly His 85 90
95 Ser Glu Arg Arg His Val Phe Gly Glu Ser Asp Glu Leu Ile Gly Gln
100 105 110 Lys Val
Ala His Ala Leu Ala Glu Gly Leu Gly Val Ile Ala Cys Ile 115
120 125 Gly Glu Lys Leu Asp Glu Arg
Glu Ala Gly Ile Thr Glu Lys Val Val 130 135
140 Phe Glu Gln Thr Lys Val Ile Ala Asp Asn Val Lys
Asp Trp Ser Lys 145 150 155
160 Val Val Leu Ala Tyr Glu Pro Val Trp Ala Ile Gly Thr Gly Lys Thr
165 170 175 Ala Thr Pro
Gln Gln Ala Gln Glu Val His Glu Lys Leu Arg Gly Trp 180
185 190 Leu Lys Ser Asn Val Ser Asp Ala
Val Ala Gln Ser Thr Arg Ile Ile 195 200
205 Tyr Gly Gly Ser Val Thr Gly Ala Thr Cys Lys Glu Leu
Ala Ser Gln 210 215 220
Pro Asp Val Asp Gly Phe Leu Val Gly Gly Ala Ser Leu Lys Pro Glu 225
230 235 240 Phe Val Asp Ile
Ile Asn Ala Lys Gln 245 71335PRTHomo
sapiens 71Met Gly Lys Val Lys Val Gly Val Asn Gly Phe Gly Arg Ile Gly Arg
1 5 10 15 Leu Val
Thr Arg Ala Ala Phe Asn Ser Gly Lys Val Asp Ile Val Ala 20
25 30 Ile Asn Asp Pro Phe Ile Asp
Leu Asn Tyr Met Val Tyr Met Phe Gln 35 40
45 Tyr Asp Ser Thr His Gly Lys Phe His Gly Thr Val
Lys Ala Glu Asn 50 55 60
Gly Lys Leu Val Ile Asn Gly Asn Pro Ile Thr Ile Phe Gln Glu Arg 65
70 75 80 Asp Pro Ser
Lys Ile Lys Trp Gly Asp Ala Gly Ala Glu Tyr Val Val 85
90 95 Glu Ser Thr Gly Val Phe Thr Thr
Met Glu Lys Ala Gly Ala His Leu 100 105
110 Gln Gly Gly Ala Lys Arg Val Ile Ile Ser Ala Pro Ser
Ala Asp Ala 115 120 125
Pro Met Phe Val Met Gly Val Asn His Glu Lys Tyr Asp Asn Ser Leu 130
135 140 Lys Ile Ile Ser
Asn Ala Ser Cys Thr Thr Asn Cys Leu Ala Pro Leu 145 150
155 160 Ala Lys Val Ile His Asp Asn Phe Gly
Ile Val Glu Gly Leu Met Thr 165 170
175 Thr Val His Ala Ile Thr Ala Thr Gln Lys Thr Val Asp Gly
Pro Ser 180 185 190
Gly Lys Leu Trp Arg Asp Gly Arg Gly Ala Leu Gln Asn Ile Ile Pro
195 200 205 Ala Ser Thr Gly
Ala Ala Lys Ala Val Gly Lys Val Ile Pro Glu Leu 210
215 220 Asn Gly Lys Leu Thr Gly Met Ala
Phe Arg Val Pro Thr Ala Asn Val 225 230
235 240 Ser Val Val Asp Leu Thr Cys Arg Leu Glu Lys Pro
Ala Lys Tyr Asp 245 250
255 Asp Ile Lys Lys Val Val Lys Gln Ala Ser Glu Gly Pro Leu Lys Gly
260 265 270 Ile Leu Gly
Tyr Thr Glu His Gln Val Val Ser Ser Asp Phe Asn Ser 275
280 285 Asp Thr His Ser Ser Thr Phe Asp
Ala Gly Ala Gly Ile Ala Leu Asn 290 295
300 Asp His Phe Val Lys Leu Ile Ser Trp Tyr Asp Asn Glu
Phe Gly Tyr 305 310 315
320 Ser Asn Arg Val Val Asp Leu Met Ala His Met Ala Ser Lys Glu
325 330 335 72408PRTHomo sapiens 72
Met Ser Lys Arg Asp Ile Val Leu Thr Asn Val Thr Val Val Gln Leu 1
5 10 15 Leu Arg Gln Pro Cys
Pro Val Thr Arg Ala Pro Pro Pro Pro Glu Pro 20
25 30 Lys Ala Glu Val Glu Pro Gln Pro Gln Pro
Glu Pro Thr Pro Val Arg 35 40
45 Glu Glu Ile Lys Pro Pro Pro Pro Pro Leu Pro Pro His Pro
Ala Thr 50 55 60
Pro Pro Pro Lys Met Val Ser Val Ala Arg Glu Leu Thr Val Gly Ile 65
70 75 80 Asn Gly Phe Gly Arg
Ile Gly Arg Leu Val Leu Arg Ala Cys Met Glu 85
90 95 Lys Gly Val Lys Val Val Ala Val Asn Asp
Pro Phe Ile Asp Pro Glu 100 105
110 Tyr Met Val Tyr Met Phe Lys Tyr Asp Ser Thr His Gly Arg Tyr
Lys 115 120 125 Gly
Ser Val Glu Phe Arg Asn Gly Gln Leu Val Val Asp Asn His Glu 130
135 140 Ile Ser Val Tyr Gln Cys
Lys Glu Pro Lys Gln Ile Pro Trp Arg Ala 145 150
155 160 Val Gly Ser Pro Tyr Val Val Glu Ser Thr Gly
Val Tyr Leu Ser Ile 165 170
175 Gln Ala Ala Ser Asp His Ile Ser Ala Gly Ala Gln Arg Val Val Ile
180 185 190 Ser Ala
Pro Ser Pro Asp Ala Pro Met Phe Val Met Gly Val Asn Glu 195
200 205 Asn Asp Tyr Asn Pro Gly Ser
Met Asn Ile Val Ser Asn Ala Ser Cys 210 215
220 Thr Thr Asn Cys Leu Ala Pro Leu Ala Lys Val Ile
His Glu Arg Phe 225 230 235
240 Gly Ile Val Glu Gly Leu Met Thr Thr Val His Ser Tyr Thr Ala Thr
245 250 255 Gln Lys Thr
Val Asp Gly Pro Ser Arg Lys Ala Trp Arg Asp Gly Arg 260
265 270 Gly Ala His Gln Asn Ile Ile Pro
Ala Ser Thr Gly Ala Ala Lys Ala 275 280
285 Val Thr Lys Val Ile Pro Glu Leu Lys Gly Lys Leu Thr
Gly Met Ala 290 295 300
Phe Arg Val Pro Thr Pro Asp Val Ser Val Val Asp Leu Thr Cys Arg 305
310 315 320 Leu Ala Gln Pro
Ala Pro Tyr Ser Ala Ile Lys Glu Ala Val Lys Ala 325
330 335 Ala Ala Lys Gly Pro Met Ala Gly Ile
Leu Ala Tyr Thr Glu Asp Glu 340 345
350 Val Val Ser Thr Asp Phe Leu Gly Asp Thr His Ser Ser Ile
Phe Asp 355 360 365
Ala Lys Ala Gly Ile Ala Leu Asn Asp Asn Phe Val Lys Leu Ile Ser 370
375 380 Trp Tyr Asp Asn Glu
Tyr Gly Tyr Ser His Arg Val Val Asp Leu Leu 385 390
395 400 Arg Tyr Met Phe Ser Arg Asp Lys
405 73434PRTHomo sapiens 73Met Ser Ile Leu Lys Ile
His Ala Arg Glu Ile Phe Asp Ser Arg Gly 1 5
10 15 Asn Pro Thr Val Glu Val Asp Leu Phe Thr Ser
Lys Gly Leu Phe Arg 20 25
30 Ala Ala Val Pro Ser Gly Ala Ser Thr Gly Ile Tyr Glu Ala Leu
Glu 35 40 45 Leu
Arg Asp Asn Asp Lys Thr Arg Tyr Met Gly Lys Gly Val Ser Lys 50
55 60 Ala Val Glu His Ile Asn
Lys Thr Ile Ala Pro Ala Leu Val Ser Lys 65 70
75 80 Lys Leu Asn Val Thr Glu Gln Glu Lys Ile Asp
Lys Leu Met Ile Glu 85 90
95 Met Asp Gly Thr Glu Asn Lys Ser Lys Phe Gly Ala Asn Ala Ile Leu
100 105 110 Gly Val
Ser Leu Ala Val Cys Lys Ala Gly Ala Val Glu Lys Gly Val 115
120 125 Pro Leu Tyr Arg His Ile Ala
Asp Leu Ala Gly Asn Ser Glu Val Ile 130 135
140 Leu Pro Val Pro Ala Phe Asn Val Ile Asn Gly Gly
Ser His Ala Gly 145 150 155
160 Asn Lys Leu Ala Met Gln Glu Phe Met Ile Leu Pro Val Gly Ala Ala
165 170 175 Asn Phe Arg
Glu Ala Met Arg Ile Gly Ala Glu Val Tyr His Asn Leu 180
185 190 Lys Asn Val Ile Lys Glu Lys Tyr
Gly Lys Asp Ala Thr Asn Val Gly 195 200
205 Asp Glu Gly Gly Phe Ala Pro Asn Ile Leu Glu Asn Lys
Glu Gly Leu 210 215 220
Glu Leu Leu Lys Thr Ala Ile Gly Lys Ala Gly Tyr Thr Asp Lys Val 225
230 235 240 Val Ile Gly Met
Asp Val Ala Ala Ser Glu Phe Phe Arg Ser Gly Lys 245
250 255 Tyr Asp Leu Asp Phe Lys Ser Pro Asp
Asp Pro Ser Arg Tyr Ile Ser 260 265
270 Pro Asp Gln Leu Ala Asp Leu Tyr Lys Ser Phe Ile Lys Asp
Tyr Pro 275 280 285
Val Val Ser Ile Glu Asp Pro Phe Asp Gln Asp Asp Trp Gly Ala Trp 290
295 300 Gln Lys Phe Thr Ala
Ser Ala Gly Ile Gln Val Val Gly Asp Asp Leu 305 310
315 320 Thr Val Thr Asn Pro Lys Arg Ile Ala Lys
Ala Val Asn Glu Lys Ser 325 330
335 Cys Asn Cys Leu Leu Leu Lys Val Asn Gln Ile Gly Ser Val Thr
Glu 340 345 350 Ser
Leu Gln Ala Cys Lys Leu Ala Gln Ala Asn Gly Trp Gly Val Met 355
360 365 Val Ser His Arg Ser Gly
Glu Thr Glu Asp Thr Phe Ile Ala Asp Leu 370 375
380 Val Val Gly Leu Cys Thr Gly Gln Ile Lys Thr
Gly Ala Pro Cys Arg 385 390 395
400 Ser Glu Arg Leu Ala Lys Tyr Asn Gln Leu Leu Arg Ile Glu Glu Glu
405 410 415 Leu Gly
Ser Lys Ala Lys Phe Ala Gly Arg Asn Phe Arg Asn Pro Leu 420
425 430 Ala Lys 74434PRTHomo
sapiens 74Met Ser Ile Glu Lys Ile Trp Ala Arg Glu Ile Leu Asp Ser Arg Gly
1 5 10 15 Asn Pro
Thr Val Glu Val Asp Leu Tyr Thr Ala Lys Gly Leu Phe Arg 20
25 30 Ala Ala Val Pro Ser Gly Ala
Ser Thr Gly Ile Tyr Glu Ala Leu Glu 35 40
45 Leu Arg Asp Gly Asp Lys Gln Arg Tyr Leu Gly Lys
Gly Val Leu Lys 50 55 60
Ala Val Asp His Ile Asn Ser Thr Ile Ala Pro Ala Leu Ile Ser Ser 65
70 75 80 Gly Leu Ser
Val Val Glu Gln Glu Lys Leu Asp Asn Leu Met Leu Glu 85
90 95 Leu Asp Gly Thr Glu Asn Lys Ser
Lys Phe Gly Ala Asn Ala Ile Leu 100 105
110 Gly Val Ser Leu Ala Val Cys Lys Ala Gly Ala Ala Glu
Arg Glu Leu 115 120 125
Pro Leu Tyr Arg His Ile Ala Gln Leu Ala Gly Asn Ser Asp Leu Ile 130
135 140 Leu Pro Val Pro
Ala Phe Asn Val Ile Asn Gly Gly Ser His Ala Gly 145 150
155 160 Asn Lys Leu Ala Met Gln Glu Phe Met
Ile Leu Pro Val Gly Ala Glu 165 170
175 Ser Phe Arg Asp Ala Met Arg Leu Gly Ala Glu Val Tyr His
Thr Leu 180 185 190
Lys Gly Val Ile Lys Asp Lys Tyr Gly Lys Asp Ala Thr Asn Val Gly
195 200 205 Asp Glu Gly Gly
Phe Ala Pro Asn Ile Leu Glu Asn Ser Glu Ala Leu 210
215 220 Glu Leu Val Lys Glu Ala Ile Asp
Lys Ala Gly Tyr Thr Glu Lys Ile 225 230
235 240 Val Ile Gly Met Asp Val Ala Ala Ser Glu Phe Tyr
Arg Asp Gly Lys 245 250
255 Tyr Asp Leu Asp Phe Lys Ser Pro Thr Asp Pro Ser Arg Tyr Ile Thr
260 265 270 Gly Asp Gln
Leu Gly Ala Leu Tyr Gln Asp Phe Val Arg Asp Tyr Pro 275
280 285 Val Val Ser Ile Glu Asp Pro Phe
Asp Gln Asp Asp Trp Ala Ala Trp 290 295
300 Ser Lys Phe Thr Ala Asn Val Gly Ile Gln Ile Val Gly
Asp Asp Leu 305 310 315
320 Thr Val Thr Asn Pro Lys Arg Ile Glu Arg Ala Val Glu Glu Lys Ala
325 330 335 Cys Asn Cys Leu
Leu Leu Lys Val Asn Gln Ile Gly Ser Val Thr Glu 340
345 350 Ala Ile Gln Ala Cys Lys Leu Ala Gln
Glu Asn Gly Trp Gly Val Met 355 360
365 Val Ser His Arg Ser Gly Glu Thr Glu Asp Thr Phe Ile Ala
Asp Leu 370 375 380
Val Val Gly Leu Cys Thr Gly Gln Ile Lys Thr Gly Ala Pro Cys Arg 385
390 395 400 Ser Glu Arg Leu Ala
Lys Tyr Asn Gln Leu Met Arg Ile Glu Glu Glu 405
410 415 Leu Gly Asp Glu Ala Arg Phe Ala Gly His
Asn Phe Arg Asn Pro Ser 420 425
430 Val Leu 75334PRTHomo sapiens 75Met Ala Thr Leu Lys Glu Lys
Leu Ile Ala Pro Val Ala Glu Glu Glu 1 5
10 15 Ala Thr Val Pro Asn Asn Lys Ile Thr Val Val
Gly Val Gly Gln Val 20 25
30 Gly Met Ala Cys Ala Ile Ser Ile Leu Gly Lys Ser Leu Ala Asp
Glu 35 40 45 Leu
Ala Leu Val Asp Val Leu Glu Asp Lys Leu Lys Gly Glu Met Met 50
55 60 Asp Leu Gln His Gly Ser
Leu Phe Leu Gln Thr Pro Lys Ile Val Ala 65 70
75 80 Asp Lys Asp Tyr Ser Val Thr Ala Asn Ser Lys
Ile Val Val Val Thr 85 90
95 Ala Gly Val Arg Gln Gln Glu Gly Glu Ser Arg Leu Asn Leu Val Gln
100 105 110 Arg Asn
Val Asn Val Phe Lys Phe Ile Ile Pro Gln Ile Val Lys Tyr 115
120 125 Ser Pro Asp Cys Ile Ile Ile
Val Val Ser Asn Pro Val Asp Ile Leu 130 135
140 Thr Tyr Val Thr Trp Lys Leu Ser Gly Leu Pro Lys
His Arg Val Ile 145 150 155
160 Gly Ser Gly Cys Asn Leu Asp Ser Ala Arg Phe Arg Tyr Leu Met Ala
165 170 175 Glu Lys Leu
Gly Ile His Pro Ser Ser Cys His Gly Trp Ile Leu Gly 180
185 190 Glu His Gly Asp Ser Ser Val Ala
Val Trp Ser Gly Val Asn Val Ala 195 200
205 Gly Val Ser Leu Gln Glu Leu Asn Pro Glu Met Gly Thr
Asp Asn Asp 210 215 220
Ser Glu Asn Trp Lys Glu Val His Lys Met Val Val Glu Ser Ala Tyr 225
230 235 240 Glu Val Ile Lys
Leu Lys Gly Tyr Thr Asn Trp Ala Ile Gly Leu Ser 245
250 255 Val Ala Asp Leu Ile Glu Ser Met Leu
Lys Asn Leu Ser Arg Ile His 260 265
270 Pro Val Ser Thr Met Val Lys Gly Met Tyr Gly Ile Glu Asn
Glu Val 275 280 285
Phe Leu Ser Leu Pro Cys Ile Leu Asn Ala Arg Gly Leu Thr Ser Val 290
295 300 Ile Asn Gln Lys Leu
Lys Asp Asp Glu Val Ala Gln Leu Lys Lys Ser 305 310
315 320 Ala Asp Thr Leu Trp Asp Ile Gln Lys Asp
Leu Lys Asp Leu 325 330
76727PRTHomo sapiens 76 Met Ala Phe Gln Lys Ala Val Lys Gly Thr Ile Leu
Val Gly Gly Gly 1 5 10
15 Ala Leu Ala Thr Val Leu Gly Leu Ser Gln Phe Ala His Tyr Arg Arg
20 25 30 Lys Gln Met
Asn Leu Ala Tyr Val Lys Ala Ala Asp Cys Ile Ser Glu 35
40 45 Pro Val Asn Arg Glu Pro Pro Ser
Arg Glu Ala Gln Leu Leu Thr Leu 50 55
60 Gln Asn Thr Ser Glu Phe Asp Ile Leu Val Ile Gly Gly
Gly Ala Thr 65 70 75
80 Gly Ser Gly Cys Ala Leu Asp Ala Val Thr Arg Gly Leu Lys Thr Ala
85 90 95 Leu Val Glu Arg
Asp Asp Phe Ser Ser Gly Thr Ser Ser Arg Ser Thr 100
105 110 Lys Leu Ile His Gly Gly Val Arg Tyr
Leu Gln Lys Ala Ile Met Lys 115 120
125 Leu Asp Ile Glu Gln Tyr Arg Met Val Lys Glu Ala Leu His
Glu Arg 130 135 140
Ala Asn Leu Leu Glu Ile Ala Pro His Leu Ser Ala Pro Leu Pro Ile 145
150 155 160 Met Leu Pro Val Tyr
Lys Trp Trp Gln Leu Pro Tyr Tyr Trp Val Gly 165
170 175 Ile Lys Leu Tyr Asp Leu Val Ala Gly Ser
Asn Cys Leu Lys Ser Ser 180 185
190 Tyr Val Leu Ser Lys Ser Arg Ala Leu Glu His Phe Pro Met Leu
Gln 195 200 205 Lys
Asp Lys Leu Val Gly Ala Ile Val Tyr Tyr Asp Gly Gln His Asn 210
215 220 Asp Ala Arg Met Asn Leu
Ala Ile Ala Leu Thr Ala Ala Arg Tyr Gly 225 230
235 240 Ala Ala Thr Ala Asn Tyr Met Glu Val Val Ser
Leu Leu Lys Lys Thr 245 250
255 Asp Pro Gln Thr Gly Lys Val His Val Ser Gly Ala Arg Cys Lys Asp
260 265 270 Val Leu
Thr Gly Gln Glu Phe Asp Val Arg Ala Lys Cys Val Ile Asn 275
280 285 Ala Thr Gly Pro Phe Thr Asp
Ser Val Arg Lys Met Asp Asp Lys Asp 290 295
300 Ala Ala Ala Ile Cys Gln Pro Ser Ala Gly Val His
Ile Val Met Pro 305 310 315
320 Gly Tyr Tyr Ser Pro Glu Ser Met Gly Leu Leu Asp Pro Ala Thr Ser
325 330 335 Asp Gly Arg
Val Ile Phe Phe Leu Pro Trp Gln Lys Met Thr Ile Ala 340
345 350 Gly Thr Thr Asp Thr Pro Thr Asp
Val Thr His His Pro Ile Pro Ser 355 360
365 Glu Glu Asp Ile Asn Phe Ile Leu Asn Glu Val Arg Asn
Tyr Leu Ser 370 375 380
Cys Asp Val Glu Val Arg Arg Gly Asp Val Leu Ala Ala Trp Ser Gly 385
390 395 400 Ile Arg Pro Leu
Val Thr Asp Pro Lys Ser Ala Asp Thr Gln Ser Ile 405
410 415 Ser Arg Asn His Val Val Asp Ile Ser
Glu Ser Gly Leu Ile Thr Ile 420 425
430 Ala Gly Gly Lys Trp Thr Thr Tyr Arg Ser Met Ala Glu Asp
Thr Ile 435 440 445
Asn Ala Ala Val Lys Thr His Asn Leu Lys Ala Gly Pro Ser Arg Thr 450
455 460 Val Gly Leu Phe Leu
Gln Gly Gly Lys Asp Trp Ser Pro Thr Leu Tyr 465 470
475 480 Ile Arg Leu Val Gln Asp Tyr Gly Leu Glu
Ser Glu Val Ala Gln His 485 490
495 Leu Ala Ala Thr Tyr Gly Asp Lys Ala Phe Glu Val Ala Lys Met
Ala 500 505 510 Ser
Val Thr Gly Lys Arg Trp Pro Ile Val Gly Val Arg Leu Val Ser 515
520 525 Glu Phe Pro Tyr Ile Glu
Ala Glu Val Lys Tyr Gly Ile Lys Glu Tyr 530 535
540 Ala Cys Thr Ala Val Asp Met Ile Ser Arg Arg
Thr Arg Leu Ala Phe 545 550 555
560 Leu Asn Val Gln Ala Ala Glu Glu Ala Leu Pro Arg Ile Val Glu Leu
565 570 575 Met Gly
Arg Glu Leu Asn Trp Asp Asp Tyr Lys Lys Gln Glu Gln Leu 580
585 590 Glu Thr Ala Arg Lys Phe Leu
Tyr Tyr Glu Met Gly Tyr Lys Ser Arg 595 600
605 Ser Glu Gln Leu Thr Asp Arg Ser Glu Ile Ser Leu
Leu Pro Ser Asp 610 615 620
Ile Asp Arg Tyr Lys Lys Arg Phe His Lys Phe Asp Ala Asp Gln Lys 625
630 635 640 Gly Phe Ile
Thr Ile Val Asp Val Gln Arg Val Leu Glu Ser Ile Asn 645
650 655 Val Gln Met Asp Glu Asn Thr Leu
His Glu Ile Leu Asn Glu Val Asp 660 665
670 Leu Asn Lys Asn Gly Gln Val Glu Leu Asn Glu Phe Leu
Gln Leu Met 675 680 685
Ser Ala Ile Gln Lys Gly Arg Val Ser Gly Ser Arg Leu Ala Ile Leu 690
695 700 Met Lys Thr Ala
Glu Glu Asn Leu Asp Arg Arg Val Pro Ile Pro Val 705 710
715 720 Asp Arg Ser Cys Gly Gly Leu
725 77727PRTHomo sapiens 77Met Ala Phe Gln Lys Ala Val
Lys Gly Thr Ile Leu Val Gly Gly Gly 1 5
10 15 Ala Leu Ala Thr Val Leu Gly Leu Ser Gln Phe
Ala His Tyr Arg Arg 20 25
30 Lys Gln Met Asn Leu Ala Tyr Val Lys Ala Ala Asp Cys Ile Ser
Glu 35 40 45 Pro
Val Asn Arg Glu Pro Pro Ser Arg Glu Ala Gln Leu Leu Thr Leu 50
55 60 Gln Asn Thr Ser Glu Phe
Asp Ile Leu Val Ile Gly Gly Gly Ala Thr 65 70
75 80 Gly Ser Gly Cys Ala Leu Asp Ala Val Thr Arg
Gly Leu Lys Thr Ala 85 90
95 Leu Val Glu Arg Asp Asp Phe Ser Ser Gly Thr Ser Ser Arg Ser Thr
100 105 110 Lys Leu
Ile His Gly Gly Val Arg Tyr Leu Gln Lys Ala Ile Met Lys 115
120 125 Leu Asp Ile Glu Gln Tyr Arg
Met Val Lys Glu Ala Leu His Glu Arg 130 135
140 Ala Asn Leu Leu Glu Ile Ala Pro His Leu Ser Ala
Pro Leu Pro Ile 145 150 155
160 Met Leu Pro Val Tyr Lys Trp Trp Gln Leu Pro Tyr Tyr Trp Val Gly
165 170 175 Ile Lys Leu
Tyr Asp Leu Val Ala Gly Ser Asn Cys Leu Lys Ser Ser 180
185 190 Tyr Val Leu Ser Lys Ser Arg Ala
Leu Glu His Phe Pro Met Leu Gln 195 200
205 Lys Asp Lys Leu Val Gly Ala Ile Val Tyr Tyr Asp Gly
Gln His Asn 210 215 220
Asp Ala Arg Met Asn Leu Ala Ile Ala Leu Thr Ala Ala Arg Tyr Gly 225
230 235 240 Ala Ala Thr Ala
Asn Tyr Met Glu Val Val Ser Leu Leu Lys Lys Thr 245
250 255 Asp Pro Gln Thr Gly Lys Val Arg Val
Ser Gly Ala Arg Cys Lys Asp 260 265
270 Val Leu Thr Gly Gln Glu Phe Asp Val Arg Ala Lys Cys Val
Ile Asn 275 280 285
Ala Thr Gly Pro Phe Thr Asp Ser Val Arg Lys Met Asp Asp Lys Asp 290
295 300 Ala Ala Ala Ile Cys
Gln Pro Ser Ala Gly Val His Ile Val Met Pro 305 310
315 320 Gly Tyr Tyr Ser Pro Glu Ser Met Gly Leu
Leu Asp Pro Ala Thr Ser 325 330
335 Asp Gly Arg Val Ile Phe Phe Leu Pro Trp Gln Lys Met Thr Ile
Ala 340 345 350 Gly
Thr Thr Asp Thr Pro Thr Asp Val Thr His His Pro Ile Pro Ser 355
360 365 Glu Glu Asp Ile Asn Phe
Ile Leu Asn Glu Val Arg Asn Tyr Leu Ser 370 375
380 Cys Asp Val Glu Val Arg Arg Gly Asp Val Leu
Ala Ala Trp Ser Gly 385 390 395
400 Ile Arg Pro Leu Val Thr Asp Pro Lys Ser Ala Asp Thr Gln Ser Ile
405 410 415 Ser Arg
Asn His Val Val Asp Ile Ser Glu Ser Gly Leu Ile Thr Ile 420
425 430 Ala Gly Gly Lys Trp Thr Thr
Tyr Arg Ser Met Ala Glu Asp Thr Ile 435 440
445 Asn Ala Ala Val Lys Thr His Asn Leu Lys Ala Gly
Pro Ser Arg Thr 450 455 460
Val Gly Leu Phe Leu Gln Gly Gly Lys Asp Trp Ser Pro Thr Leu Tyr 465
470 475 480 Ile Arg Leu
Val Gln Asp Tyr Gly Leu Glu Ser Glu Val Ala Gln His 485
490 495 Leu Ala Ala Thr Tyr Gly Asp Lys
Ala Phe Glu Val Ala Lys Met Ala 500 505
510 Ser Val Thr Gly Lys Arg Trp Pro Ile Val Gly Val Arg
Leu Val Ser 515 520 525
Glu Phe Pro Tyr Ile Glu Ala Glu Val Lys Tyr Gly Ile Lys Glu Tyr 530
535 540 Ala Cys Thr Ala
Val Asp Met Ile Ser Arg Arg Thr Arg Leu Ala Phe 545 550
555 560 Leu Asn Val Gln Ala Ala Glu Glu Ala
Leu Pro Arg Ile Val Glu Leu 565 570
575 Met Gly Arg Glu Leu Asn Trp Asp Asp Tyr Lys Lys Gln Glu
Gln Leu 580 585 590
Glu Thr Ala Arg Lys Phe Leu Tyr Tyr Glu Met Gly Tyr Lys Ser Arg
595 600 605 Ser Glu Gln Leu
Thr Asp Arg Ser Glu Ile Ser Leu Leu Pro Ser Asp 610
615 620 Ile Asp Arg Tyr Lys Lys Arg Phe
His Lys Phe Asp Ala Asp Gln Lys 625 630
635 640 Gly Phe Ile Thr Ile Val Asp Val Gln Arg Val Leu
Glu Ser Ile Asn 645 650
655 Val Gln Met Asp Glu Asn Thr Leu His Glu Ile Leu Asn Glu Val Asp
660 665 670 Leu Asn Lys
Asn Gly Gln Val Glu Leu Asn Glu Phe Leu Gln Leu Met 675
680 685 Ser Ala Ile Gln Lys Gly Arg Val
Ser Gly Ser Arg Leu Ala Ile Leu 690 695
700 Met Lys Thr Ala Glu Glu Asn Leu Asp Arg Arg Val Pro
Ile Pro Val 705 710 715
720 Asp Arg Ser Cys Gly Gly Leu 725 78373PRTHomo
sapiens 78Met Thr Thr Ser Ala Ser Ser His Leu Asn Lys Gly Ile Lys Gln Val
1 5 10 15 Tyr Met
Ser Leu Pro Gln Gly Glu Lys Val Gln Ala Met Tyr Ile Trp 20
25 30 Ile Asp Gly Thr Gly Glu Gly
Leu Arg Cys Lys Thr Arg Thr Leu Asp 35 40
45 Ser Glu Pro Lys Cys Val Glu Glu Leu Pro Glu Trp
Asn Phe Asp Gly 50 55 60
Ser Ser Thr Leu Gln Ser Glu Gly Ser Asn Ser Asp Met Tyr Leu Val 65
70 75 80 Pro Ala Ala
Met Phe Arg Asp Pro Phe Arg Lys Asp Pro Asn Lys Leu 85
90 95 Val Leu Cys Glu Val Phe Lys Tyr
Asn Arg Arg Pro Ala Glu Thr Asn 100 105
110 Leu Arg His Thr Cys Lys Arg Ile Met Asp Met Val Ser
Asn Gln His 115 120 125
Pro Trp Phe Gly Met Glu Gln Glu Tyr Thr Leu Met Gly Thr Asp Gly 130
135 140 His Pro Phe Gly
Trp Pro Ser Asn Gly Phe Pro Gly Pro Gln Gly Pro 145 150
155 160 Tyr Tyr Cys Gly Val Gly Ala Asp Arg
Ala Tyr Gly Arg Asp Ile Val 165 170
175 Glu Ala His Tyr Arg Ala Cys Leu Tyr Ala Gly Val Lys Ile
Ala Gly 180 185 190
Thr Asn Ala Glu Val Met Pro Ala Gln Trp Glu Phe Gln Ile Gly Pro
195 200 205 Cys Glu Gly Ile
Ser Met Gly Asp His Leu Trp Val Ala Arg Phe Ile 210
215 220 Leu His Arg Val Cys Glu Asp Phe
Gly Val Ile Ala Thr Phe Asp Pro 225 230
235 240 Lys Pro Ile Pro Gly Asn Trp Asn Gly Ala Gly Cys
His Thr Asn Phe 245 250
255 Ser Thr Lys Ala Met Arg Glu Glu Asn Gly Leu Lys Tyr Ile Glu Glu
260 265 270 Ala Ile Glu
Lys Leu Ser Lys Arg His Gln Tyr His Ile Arg Ala Tyr 275
280 285 Asp Pro Lys Gly Gly Leu Asp Asn
Ala Arg Arg Leu Thr Gly Phe His 290 295
300 Glu Thr Ser Asn Ile Asn Asp Phe Ser Ala Gly Val Ala
Asn Arg Ser 305 310 315
320 Ala Ser Ile Arg Ile Pro Arg Thr Val Gly Gln Glu Lys Lys Gly Tyr
325 330 335 Phe Glu Asp Arg
Arg Pro Ser Ala Asn Cys Asp Pro Phe Ser Val Thr 340
345 350 Glu Ala Leu Ile Arg Thr Cys Leu Leu
Asn Glu Thr Gly Asp Glu Pro 355 360
365 Phe Gln Tyr Lys Asn 370 79373PRTHomo
sapiens 79Met Thr Thr Ser Ala Ser Ser His Leu Asn Lys Gly Ile Lys Gln Val
1 5 10 15 Tyr Met
Ser Leu Pro Gln Gly Glu Lys Val Gln Ala Met Tyr Ile Trp 20
25 30 Ile Asp Gly Thr Gly Glu Gly
Leu Arg Cys Lys Thr Arg Thr Leu Asp 35 40
45 Ser Glu Pro Lys Cys Val Glu Glu Leu Pro Glu Trp
Asn Phe Asp Gly 50 55 60
Ser Ser Thr Leu Gln Ser Glu Gly Ser Asn Ser Asp Met Tyr Leu Val 65
70 75 80 Pro Ala Ala
Met Phe Arg Asp Pro Phe Arg Lys Asp Pro Asn Lys Leu 85
90 95 Val Leu Cys Glu Val Phe Lys Tyr
Asn Arg Arg Pro Ala Glu Thr Asn 100 105
110 Leu Arg His Thr Cys Lys Arg Ile Met Asp Met Val Ser
Asn Gln His 115 120 125
Pro Trp Phe Gly Met Glu Gln Glu Tyr Thr Leu Met Gly Thr Asp Gly 130
135 140 His Pro Phe Gly
Trp Pro Ser Asn Gly Phe Pro Gly Pro Gln Gly Pro 145 150
155 160 Tyr Tyr Cys Gly Val Gly Ala Asp Arg
Ala Tyr Gly Arg Asp Ile Val 165 170
175 Glu Ala His Tyr Arg Ala Cys Leu Tyr Ala Gly Val Lys Ile
Ala Gly 180 185 190
Thr Asn Ala Glu Val Met Pro Ala Gln Trp Glu Phe Gln Ile Gly Pro
195 200 205 Cys Glu Gly Ile
Ser Met Gly Asp His Leu Trp Val Ala Arg Phe Ile 210
215 220 Leu His Arg Val Cys Glu Asp Phe
Gly Val Ile Ala Thr Phe Asp Pro 225 230
235 240 Lys Pro Ile Pro Gly Asn Trp Asn Gly Ala Gly Cys
His Thr Asn Phe 245 250
255 Ser Thr Lys Ala Met Arg Glu Glu Asn Gly Leu Lys Tyr Ile Glu Glu
260 265 270 Ala Ile Glu
Lys Leu Ser Lys Arg His Gln Tyr His Ile Arg Ala Tyr 275
280 285 Asp Pro Lys Gly Gly Leu Asp Asn
Ala Arg Arg Leu Thr Gly Phe His 290 295
300 Glu Thr Ser Asn Ile Asn Asp Phe Ser Ala Gly Val Ala
Asn Arg Ser 305 310 315
320 Ala Ser Ile Arg Ile Pro Arg Thr Val Gly Gln Glu Lys Lys Gly Tyr
325 330 335 Phe Glu Asp Arg
Arg Pro Ser Ala Asn Cys Asp Pro Phe Ser Val Thr 340
345 350 Glu Ala Leu Ile Arg Thr Cys Leu Leu
Asn Glu Thr Gly Asp Glu Pro 355 360
365 Phe Gln Tyr Lys Asn 370 80647PRTHomo
sapiens 80Met Trp Arg Val Cys Ala Arg Arg Ala Gln Asn Val Ala Pro Trp Ala
1 5 10 15 Gly Leu
Glu Ala Arg Trp Thr Ala Leu Gln Glu Val Pro Gly Thr Pro 20
25 30 Arg Val Thr Ser Arg Ser Gly
Pro Ala Pro Ala Arg Arg Asn Ser Val 35 40
45 Thr Thr Gly Tyr Gly Gly Val Arg Ala Leu Cys Gly
Trp Thr Pro Ser 50 55 60
Ser Gly Ala Thr Pro Arg Asn Arg Leu Leu Leu Gln Leu Leu Gly Ser 65
70 75 80 Pro Gly Arg
Arg Tyr Tyr Ser Leu Pro Pro His Gln Lys Val Pro Leu 85
90 95 Pro Ser Leu Ser Pro Thr Met Gln
Ala Gly Thr Ile Ala Arg Trp Glu 100 105
110 Lys Lys Glu Gly Asp Lys Ile Asn Glu Gly Asp Leu Ile
Ala Glu Val 115 120 125
Glu Thr Asp Lys Ala Thr Val Gly Phe Glu Ser Leu Glu Glu Cys Tyr 130
135 140 Met Ala Lys Ile
Leu Val Ala Glu Gly Thr Arg Asp Val Pro Ile Gly 145 150
155 160 Ala Ile Ile Cys Ile Thr Val Gly Lys
Pro Glu Asp Ile Glu Ala Phe 165 170
175 Lys Asn Tyr Thr Leu Asp Ser Ser Ala Ala Pro Thr Pro Gln
Ala Ala 180 185 190
Pro Ala Pro Thr Pro Ala Ala Thr Ala Ser Pro Pro Thr Pro Ser Ala
195 200 205 Gln Ala Pro Gly
Ser Ser Tyr Pro Pro His Met Gln Val Leu Leu Pro 210
215 220 Ala Leu Ser Pro Thr Met Thr Met
Gly Thr Val Gln Arg Trp Glu Lys 225 230
235 240 Lys Val Gly Glu Lys Leu Ser Glu Gly Asp Leu Leu
Ala Glu Ile Glu 245 250
255 Thr Asp Lys Ala Thr Ile Gly Phe Glu Val Gln Glu Glu Gly Tyr Leu
260 265 270 Ala Lys Ile
Leu Val Pro Glu Gly Thr Arg Asp Val Pro Leu Gly Thr 275
280 285 Pro Leu Cys Ile Ile Val Glu Lys
Glu Ala Asp Ile Ser Ala Phe Ala 290 295
300 Asp Tyr Arg Pro Thr Glu Val Thr Asp Leu Lys Pro Gln
Val Pro Pro 305 310 315
320 Pro Thr Pro Pro Pro Val Ala Ala Val Pro Pro Thr Pro Gln Pro Leu
325 330 335 Ala Pro Thr Pro
Ser Ala Pro Cys Pro Ala Thr Pro Ala Gly Pro Lys 340
345 350 Gly Arg Val Phe Val Ser Pro Leu Ala
Lys Lys Leu Ala Val Glu Lys 355 360
365 Gly Ile Asp Leu Thr Gln Val Lys Gly Thr Gly Pro Asp Gly
Arg Ile 370 375 380
Thr Lys Lys Asp Ile Asp Ser Phe Val Pro Ser Lys Val Ala Pro Ala 385
390 395 400 Pro Ala Ala Val Val
Pro Pro Thr Gly Pro Gly Met Ala Pro Val Pro 405
410 415 Thr Gly Val Phe Thr Asp Ile Pro Ile Ser
Asn Ile Arg Arg Val Ile 420 425
430 Ala Gln Arg Leu Met Gln Ser Lys Gln Thr Ile Pro His Tyr Tyr
Leu 435 440 445 Ser
Ile Asp Val Asn Met Gly Glu Val Leu Leu Val Arg Lys Glu Leu 450
455 460 Asn Lys Ile Leu Glu Gly
Arg Ser Lys Ile Ser Val Asn Asp Phe Ile 465 470
475 480 Ile Lys Ala Ser Ala Leu Ala Cys Leu Lys Val
Pro Glu Ala Asn Ser 485 490
495 Ser Trp Met Asp Thr Val Ile Arg Gln Asn His Val Val Asp Val Ser
500 505 510 Val Ala
Val Ser Thr Pro Ala Gly Leu Ile Thr Pro Ile Val Phe Asn 515
520 525 Ala His Ile Lys Gly Val Glu
Thr Ile Ala Asn Asp Val Val Ser Leu 530 535
540 Ala Thr Lys Ala Arg Glu Gly Lys Leu Gln Pro His
Glu Phe Gln Gly 545 550 555
560 Gly Thr Phe Thr Ile Ser Asn Leu Gly Met Phe Gly Ile Lys Asn Phe
565 570 575 Ser Ala Ile
Ile Asn Pro Pro Gln Ala Cys Ile Leu Ala Ile Gly Ala 580
585 590 Ser Glu Asp Lys Leu Val Pro Ala
Asp Asn Glu Lys Gly Phe Asp Val 595 600
605 Ala Ser Met Met Ser Val Thr Leu Ser Cys Asp His Arg
Val Val Asp 610 615 620
Gly Ala Val Gly Ala Gln Trp Leu Ala Glu Phe Arg Lys Tyr Leu Glu 625
630 635 640 Lys Pro Ile Thr
Met Leu Leu 645 81366PRTHomo sapiens 81Met Ala
Gly Pro Ala Trp Ile Ser Lys Val Ser Arg Leu Leu Gly Ala 1 5
10 15 Phe His Asn Pro Lys Gln Val
Thr Arg Gly Phe Thr Gly Gly Val Gln 20 25
30 Thr Val Thr Leu Ile Pro Gly Asp Gly Ile Gly Pro
Glu Ile Ser Ala 35 40 45
Ala Val Met Lys Ile Phe Asp Ala Ala Lys Ala Pro Ile Gln Trp Glu
50 55 60 Glu Arg Asn
Val Thr Ala Ile Gln Gly Pro Gly Gly Lys Trp Met Ile 65
70 75 80 Pro Ser Glu Ala Lys Glu Ser
Met Asp Lys Asn Lys Met Gly Leu Lys 85
90 95 Gly Pro Leu Lys Thr Pro Ile Ala Ala Gly His
Pro Ser Met Asn Leu 100 105
110 Leu Leu Arg Lys Thr Phe Asp Leu Tyr Ala Asn Val Arg Pro Cys
Val 115 120 125 Ser
Ile Glu Gly Tyr Lys Thr Pro Tyr Thr Asp Val Asn Ile Val Thr 130
135 140 Ile Arg Glu Asn Thr Glu
Gly Glu Tyr Ser Gly Ile Glu His Val Ile 145 150
155 160 Val Asp Gly Val Val Gln Ser Ile Lys Leu Ile
Thr Glu Gly Ala Ser 165 170
175 Lys Arg Ile Ala Glu Phe Ala Phe Glu Tyr Ala Arg Asn Asn His Arg
180 185 190 Ser Asn
Val Thr Ala Val His Lys Ala Asn Ile Met Arg Met Ser Asp 195
200 205 Gly Leu Phe Leu Gln Lys Cys
Arg Glu Val Ala Glu Ser Cys Lys Asp 210 215
220 Ile Lys Phe Asn Glu Met Tyr Leu Asp Thr Val Cys
Leu Asn Met Val 225 230 235
240 Gln Asp Pro Ser Gln Phe Asp Val Leu Val Met Pro Asn Leu Tyr Gly
245 250 255 Asp Ile Leu
Ser Asp Leu Cys Ala Gly Leu Ile Gly Gly Leu Gly Val 260
265 270 Thr Pro Ser Gly Asn Ile Gly Ala
Asn Gly Val Ala Ile Phe Glu Ser 275 280
285 Val His Gly Thr Ala Pro Asp Ile Ala Gly Lys Asp Met
Ala Asn Pro 290 295 300
Thr Ala Leu Leu Leu Ser Ala Val Met Met Leu Arg His Met Gly Leu 305
310 315 320 Phe Asp His Ala
Ala Arg Ile Glu Ala Ala Cys Phe Ala Thr Ile Lys 325
330 335 Asp Gly Lys Ser Leu Thr Lys Asp Leu
Gly Gly Asn Ala Lys Cys Ser 340 345
350 Asp Phe Thr Glu Glu Ile Cys Arg Arg Val Lys Asp Leu Asp
355 360 365 82334PRTHomo
sapiens 82Met Ser Glu Pro Ile Arg Val Leu Val Thr Gly Ala Ala Gly Gln Ile
1 5 10 15 Ala Tyr
Ser Leu Leu Tyr Ser Ile Gly Asn Gly Ser Val Phe Gly Lys 20
25 30 Asp Gln Pro Ile Ile Leu Val
Leu Leu Asp Ile Thr Pro Met Met Gly 35 40
45 Val Leu Asp Gly Val Leu Met Glu Leu Gln Asp Cys
Ala Leu Pro Leu 50 55 60
Leu Lys Asp Val Ile Ala Thr Asp Lys Glu Asp Val Ala Phe Lys Asp 65
70 75 80 Leu Asp Val
Ala Ile Leu Val Gly Ser Met Pro Arg Arg Glu Gly Met 85
90 95 Glu Arg Lys Asp Leu Leu Lys Ala
Asn Val Lys Ile Phe Lys Ser Gln 100 105
110 Gly Ala Ala Leu Asp Lys Tyr Ala Lys Lys Ser Val Lys
Val Ile Val 115 120 125
Val Gly Asn Pro Ala Asn Thr Asn Cys Leu Thr Ala Ser Lys Ser Ala 130
135 140 Pro Ser Ile Pro
Lys Glu Asn Phe Ser Cys Leu Thr Arg Leu Asp His 145 150
155 160 Asn Arg Ala Lys Ala Gln Ile Ala Leu
Lys Leu Gly Val Thr Ala Asn 165 170
175 Asp Val Lys Asn Val Ile Ile Trp Gly Asn His Ser Ser Thr
Gln Tyr 180 185 190
Pro Asp Val Asn His Ala Lys Val Lys Leu Gln Gly Lys Glu Val Gly
195 200 205 Val Tyr Glu Ala
Leu Lys Asp Asp Ser Trp Leu Lys Gly Glu Phe Val 210
215 220 Thr Thr Val Gln Gln Arg Gly Ala
Ala Val Ile Lys Ala Arg Lys Leu 225 230
235 240 Ser Ser Ala Met Ser Ala Ala Lys Ala Ile Cys Asp
His Val Arg Asp 245 250
255 Ile Trp Phe Gly Thr Pro Glu Gly Glu Phe Val Ser Met Gly Val Ile
260 265 270 Ser Asp Gly
Asn Ser Tyr Gly Val Pro Asp Asp Leu Leu Tyr Ser Phe 275
280 285 Pro Val Val Ile Lys Asn Lys Thr
Trp Lys Phe Val Glu Gly Leu Pro 290 295
300 Ile Asn Asp Phe Ser Arg Glu Lys Met Asp Leu Thr Ala
Lys Glu Leu 305 310 315
320 Thr Glu Glu Lys Glu Ser Ala Phe Glu Phe Leu Ser Ser Ala
325 330 83172PRTHomo sapiens 83 Met Pro
Gly Ile Val Glu Leu Pro Thr Leu Glu Glu Leu Lys Val Asp 1 5
10 15 Glu Val Lys Ile Ser Ser Ala
Val Leu Lys Ala Ala Ala His His Tyr 20 25
30 Gly Ala Gln Cys Asp Lys Pro Asn Lys Glu Phe Met
Leu Cys Arg Trp 35 40 45
Glu Glu Lys Asp Pro Arg Arg Cys Leu Glu Glu Gly Lys Leu Val Asn
50 55 60 Lys Cys Ala
Leu Asp Phe Phe Arg Gln Ile Lys Arg His Cys Ala Glu 65
70 75 80 Pro Phe Thr Glu Tyr Trp Thr
Cys Ile Asp Tyr Thr Gly Gln Gln Leu 85
90 95 Phe Arg His Cys Arg Lys Gln Gln Ala Lys Phe
Asp Glu Cys Val Leu 100 105
110 Asp Lys Leu Gly Trp Val Arg Pro Asp Leu Gly Glu Leu Ser Lys
Val 115 120 125 Thr
Lys Val Lys Thr Asp Arg Pro Leu Pro Glu Asn Pro Tyr His Ser 130
135 140 Arg Pro Arg Pro Asp Pro
Ser Pro Glu Ile Glu Gly Asp Leu Gln Pro 145 150
155 160 Ala Thr His Gly Ser Arg Phe Tyr Phe Trp Thr
Lys 165 170 84727PRTHomo sapiens
84 Met Leu Arg Ile Pro Val Arg Lys Ala Leu Val Gly Leu Ser Lys Ser 1
5 10 15 Pro Lys Gly Cys
Val Arg Thr Thr Ala Thr Ala Ala Ser Asn Leu Ile 20
25 30 Glu Val Phe Val Asp Gly Gln Ser Val
Met Val Glu Pro Gly Thr Thr 35 40
45 Val Leu Gln Ala Cys Glu Lys Val Gly Met Gln Ile Pro Arg
Phe Cys 50 55 60
Tyr His Glu Arg Leu Ser Val Ala Gly Asn Cys Arg Met Cys Leu Val 65
70 75 80 Glu Ile Glu Lys Ala
Pro Lys Val Val Ala Ala Cys Ala Met Pro Val 85
90 95 Met Lys Gly Trp Asn Ile Leu Thr Asn Ser
Glu Lys Ser Lys Lys Ala 100 105
110 Arg Glu Gly Val Met Glu Phe Leu Leu Ala Asn His Pro Leu Asp
Cys 115 120 125 Pro
Ile Cys Asp Gln Gly Gly Glu Cys Asp Leu Gln Asp Gln Ser Met 130
135 140 Met Phe Gly Asn Asp Arg
Ser Arg Phe Leu Glu Gly Lys Arg Ala Val 145 150
155 160 Glu Asp Lys Asn Ile Gly Pro Leu Val Lys Thr
Ile Met Thr Arg Cys 165 170
175 Ile Gln Cys Thr Arg Cys Ile Arg Phe Ala Ser Glu Ile Ala Gly Val
180 185 190 Asp Asp
Leu Gly Thr Thr Gly Arg Gly Asn Asp Met Gln Val Gly Thr 195
200 205 Tyr Ile Glu Lys Met Phe Met
Ser Glu Leu Ser Gly Asn Ile Ile Asp 210 215
220 Ile Cys Pro Val Gly Ala Leu Thr Ser Lys Pro Tyr
Ala Phe Thr Ala 225 230 235
240 Arg Pro Trp Glu Thr Arg Lys Thr Glu Ser Ile Asp Val Met Asp Ala
245 250 255 Val Gly Ser
Asn Ile Val Val Ser Thr Arg Thr Gly Glu Val Met Arg 260
265 270 Ile Leu Pro Arg Met His Glu Asp
Ile Asn Glu Glu Trp Ile Ser Asp 275 280
285 Lys Thr Arg Phe Ala Tyr Asp Gly Leu Lys Arg Gln Arg
Leu Thr Glu 290 295 300
Pro Met Val Arg Asn Glu Lys Gly Leu Leu Thr Tyr Thr Ser Trp Glu 305
310 315 320 Asp Ala Leu Ser
Arg Val Ala Gly Met Leu Gln Ser Phe Gln Gly Lys 325
330 335 Asp Val Ala Ala Ile Ala Gly Gly Leu
Val Asp Ala Glu Ala Leu Val 340 345
350 Ala Leu Lys Asp Leu Leu Asn Arg Val Asp Ser Asp Thr Leu
Cys Thr 355 360 365
Glu Glu Val Phe Pro Thr Ala Gly Ala Gly Thr Asp Leu Arg Ser Asn 370
375 380 Tyr Leu Leu Asn Thr
Thr Ile Ala Gly Val Glu Glu Ala Asp Val Val 385 390
395 400 Leu Leu Val Gly Thr Asn Pro Arg Phe Glu
Ala Pro Leu Phe Asn Ala 405 410
415 Arg Ile Arg Lys Ser Trp Leu His Asn Asp Leu Lys Val Ala Leu
Ile 420 425 430 Gly
Ser Pro Val Asp Leu Thr Tyr Thr Tyr Asp His Leu Gly Asp Ser 435
440 445 Pro Lys Ile Leu Gln Asp
Ile Ala Ser Gly Ser His Pro Phe Ser Gln 450 455
460 Val Leu Lys Glu Ala Lys Lys Pro Met Val Val
Leu Gly Ser Ser Ala 465 470 475
480 Leu Gln Arg Asn Asp Gly Ala Ala Ile Leu Ala Ala Val Ser Ser Ile
485 490 495 Ala Gln
Lys Ile Arg Met Thr Ser Gly Val Thr Gly Asp Trp Lys Val 500
505 510 Met Asn Ile Leu His Arg Ile
Ala Ser Gln Val Ala Ala Leu Asp Leu 515 520
525 Gly Tyr Lys Pro Gly Val Glu Ala Ile Arg Lys Asn
Pro Pro Lys Val 530 535 540
Leu Phe Leu Leu Gly Ala Asp Gly Gly Cys Ile Thr Arg Gln Asp Leu 545
550 555 560 Pro Lys Asp
Cys Phe Ile Ile Tyr Gln Gly His His Gly Asp Val Gly 565
570 575 Ala Pro Ile Ala Asp Val Ile Leu
Pro Gly Ala Ala Tyr Thr Glu Lys 580 585
590 Ser Ala Thr Tyr Val Asn Thr Glu Gly Arg Ala Gln Gln
Thr Lys Val 595 600 605
Ala Val Thr Pro Pro Gly Leu Ala Arg Glu Asp Trp Lys Ile Ile Arg 610
615 620 Ala Leu Ser Glu
Ile Ala Gly Met Thr Leu Pro Tyr Asp Thr Leu Asp 625 630
635 640 Gln Val Arg Asn Arg Leu Glu Glu Val
Ser Pro Asn Leu Val Arg Tyr 645 650
655 Asp Asp Ile Glu Gly Ala Asn Tyr Phe Gln Gln Ala Asn Glu
Leu Ser 660 665 670
Lys Leu Val Asn Gln Gln Leu Leu Ala Asp Pro Leu Val Pro Pro Gln
675 680 685 Leu Thr Ile Lys
Asp Phe Tyr Met Thr Asp Ser Ile Ser Arg Ala Ser 690
695 700 Gln Thr Met Ala Lys Cys Val Lys
Ala Val Thr Glu Gly Ala Gln Ala 705 710
715 720 Val Glu Glu Pro Ser Ile Cys 725
85210PRTHomo sapiens 85Met Arg Cys Leu Thr Thr Pro Met Leu Leu Arg
Ala Leu Ala Gln Ala 1 5 10
15 Ala Arg Ala Gly Pro Pro Gly Gly Arg Ser Leu His Ser Ser Ala Val
20 25 30 Ala Ala
Thr Tyr Lys Tyr Val Asn Met Gln Asp Pro Glu Met Asp Met 35
40 45 Lys Ser Val Thr Asp Arg Ala
Ala Arg Thr Leu Leu Trp Thr Glu Leu 50 55
60 Phe Arg Gly Leu Gly Met Thr Leu Ser Tyr Leu Phe
Arg Glu Pro Ala 65 70 75
80 Thr Ile Asn Tyr Pro Phe Glu Lys Gly Pro Leu Ser Pro Arg Phe Arg
85 90 95 Gly Glu His
Ala Leu Arg Arg Tyr Pro Ser Gly Glu Glu Arg Cys Ile 100
105 110 Ala Cys Lys Leu Cys Glu Ala Ile
Cys Pro Ala Gln Ala Ile Thr Ile 115 120
125 Glu Ala Glu Pro Arg Ala Asp Gly Ser Arg Arg Thr Thr
Arg Tyr Asp 130 135 140
Ile Asp Met Thr Lys Cys Ile Tyr Cys Gly Phe Cys Gln Glu Ala Cys 145
150 155 160 Pro Val Asp Ala
Ile Val Glu Gly Pro Asn Phe Glu Phe Ser Thr Glu 165
170 175 Thr His Glu Glu Leu Leu Tyr Asn Lys
Glu Lys Leu Leu Asn Asn Gly 180 185
190 Asp Lys Trp Glu Ala Glu Ile Ala Ala Asn Ile Gln Ala Asp
Tyr Leu 195 200 205
Tyr Arg 210 86480PRTHomo sapiens 86Met Ala Ala Ser Val Val Cys Arg
Ala Ala Thr Ala Gly Ala Gln Val 1 5 10
15 Leu Leu Arg Ala Arg Arg Ser Pro Ala Leu Leu Arg Thr
Pro Ala Leu 20 25 30
Arg Ser Thr Ala Thr Phe Ala Gln Ala Leu Gln Phe Val Pro Glu Thr
35 40 45 Gln Val Ser Leu
Leu Asp Asn Gly Leu Arg Val Ala Ser Glu Gln Ser 50
55 60 Ser Gln Pro Thr Cys Thr Val Gly
Val Trp Ile Asp Val Gly Ser Arg 65 70
75 80 Phe Glu Thr Glu Lys Asn Asn Gly Ala Gly Tyr Phe
Leu Glu His Leu 85 90
95 Ala Phe Lys Gly Thr Lys Asn Arg Pro Gly Ser Ala Leu Glu Lys Glu
100 105 110 Val Glu Ser
Met Gly Ala His Leu Asn Ala Tyr Ser Thr Arg Glu His 115
120 125 Thr Ala Tyr Tyr Ile Lys Ala Leu
Ser Lys Asp Leu Pro Lys Ala Val 130 135
140 Glu Leu Leu Gly Asp Ile Val Gln Asn Cys Ser Leu Glu
Asp Ser Gln 145 150 155
160 Ile Glu Lys Glu Arg Asp Val Ile Leu Arg Glu Met Gln Glu Asn Asp
165 170 175 Ala Ser Met Arg
Asp Val Val Phe Asn Tyr Leu His Ala Thr Ala Phe 180
185 190 Gln Gly Thr Pro Leu Ala Gln Ala Val
Glu Gly Pro Ser Glu Asn Val 195 200
205 Arg Lys Leu Ser Arg Ala Asp Leu Thr Glu Tyr Leu Ser Thr
His Tyr 210 215 220
Lys Ala Pro Arg Met Val Leu Ala Ala Ala Gly Gly Val Glu His Gln 225
230 235 240 Gln Leu Leu Asp Leu
Ala Gln Lys His Leu Gly Gly Ile Pro Trp Thr 245
250 255 Tyr Ala Glu Asp Ala Val Pro Thr Leu Thr
Pro Cys Arg Phe Thr Gly 260 265
270 Ser Glu Ile Arg His Arg Asp Asp Ala Leu Pro Phe Ala His Val
Ala 275 280 285 Ile
Ala Val Glu Gly Pro Gly Trp Ala Ser Pro Asp Asn Val Ala Leu 290
295 300 Gln Val Ala Asn Ala Ile
Ile Gly His Tyr Asp Cys Thr Tyr Gly Gly 305 310
315 320 Gly Val His Leu Ser Ser Pro Leu Ala Ser Gly
Ala Val Ala Asn Lys 325 330
335 Leu Cys Gln Ser Phe Gln Thr Phe Ser Ile Cys Tyr Ala Glu Thr Gly
340 345 350 Leu Leu
Gly Ala His Phe Val Cys Asp Arg Met Lys Ile Asp Asp Met 355
360 365 Met Phe Val Leu Gln Gly Gln
Trp Met Arg Leu Cys Thr Ser Ala Thr 370 375
380 Glu Ser Glu Val Ala Arg Gly Lys Asn Ile Leu Arg
Asn Ala Leu Val 385 390 395
400 Ser His Leu Asp Gly Thr Thr Pro Val Cys Glu Asp Ile Gly Arg Ser
405 410 415 Leu Leu Thr
Tyr Gly Arg Arg Ile Pro Leu Ala Glu Trp Glu Ser Arg 420
425 430 Ile Ala Glu Val Asp Ala Ser Val
Val Arg Glu Ile Cys Ser Lys Tyr 435 440
445 Ile Tyr Asp Gln Cys Pro Ala Val Ala Gly Tyr Gly Pro
Ile Glu Gln 450 455 460
Leu Pro Asp Tyr Asn Arg Ile Arg Ser Gly Met Phe Trp Leu Arg Phe 465
470 475 480 87161PRTHomo
sapiens 87Met Ala Gly Arg Lys Leu Ala Leu Lys Thr Ile Asp Trp Val Ala Phe
1 5 10 15 Ala Glu
Ile Ile Pro Gln Asn Gln Lys Ala Ile Ala Ser Ser Leu Lys 20
25 30 Ser Trp Asn Glu Thr Leu Thr
Ser Arg Leu Ala Ala Leu Pro Glu Asn 35 40
45 Pro Pro Ala Ile Asp Trp Ala Tyr Tyr Lys Ala Asn
Val Ala Lys Ala 50 55 60
Gly Leu Val Asp Asp Phe Glu Lys Lys Phe Asn Ala Leu Lys Val Pro 65
70 75 80 Val Pro Glu
Asp Lys Tyr Thr Ala Gln Val Asp Ala Glu Glu Lys Glu 85
90 95 Asp Val Lys Ser Cys Ala Glu Trp
Val Ser Leu Ser Lys Ala Arg Ile 100 105
110 Val Glu Tyr Glu Lys Glu Met Glu Lys Met Lys Asn Leu
Ile Pro Phe 115 120 125
Asp Gln Met Thr Ile Glu Asp Leu Asn Glu Ala Phe Pro Glu Thr Lys 130
135 140 Leu Asp Lys Lys
Lys Tyr Pro Tyr Trp Pro His Gln Pro Ile Glu Asn 145 150
155 160 Leu 88137PRTHomo sapiens 88Met Ala
Gly Arg Lys Leu Ala Leu Lys Thr Ile Asp Trp Val Ala Phe 1 5
10 15 Ala Glu Ile Ile Pro Gln Asn
Gln Lys Ala Ile Ala Ser Ser Leu Lys 20 25
30 Ser Trp Asn Glu Thr Leu Thr Ser Arg Leu Ala Ala
Leu Pro Glu Asn 35 40 45
Pro Pro Ala Ile Asp Trp Ala Tyr Tyr Lys Ala Asn Val Ala Lys Ala
50 55 60 Gly Leu Val
Asp Asp Phe Glu Lys Lys Val Lys Ser Cys Ala Glu Trp 65
70 75 80 Val Ser Leu Ser Lys Ala Arg
Ile Val Glu Tyr Glu Lys Glu Met Glu 85
90 95 Lys Met Lys Asn Leu Ile Pro Phe Asp Gln Met
Thr Ile Glu Asp Leu 100 105
110 Asn Glu Ala Phe Pro Glu Thr Lys Leu Asp Lys Lys Lys Tyr Pro
Tyr 115 120 125 Trp
Pro His Gln Pro Ile Glu Asn Leu 130 135
89381PRTHomo sapiens 89Met Pro Phe Ser Asn Ser His Asn Ala Leu Lys Leu
Arg Phe Pro Ala 1 5 10
15 Glu Asp Glu Phe Pro Asp Leu Ser Ala His Asn Asn His Met Ala Lys
20 25 30 Val Leu Thr
Pro Glu Leu Tyr Ala Glu Leu Arg Ala Lys Ser Thr Pro 35
40 45 Ser Gly Phe Thr Leu Asp Asp Val
Ile Gln Thr Gly Val Asp Asn Pro 50 55
60 Gly His Pro Tyr Ile Met Thr Val Gly Cys Val Ala Gly
Asp Glu Glu 65 70 75
80 Ser Tyr Glu Val Phe Lys Asp Leu Phe Asp Pro Ile Ile Glu Asp Arg
85 90 95 His Gly Gly Tyr
Lys Pro Ser Asp Glu His Lys Thr Asp Leu Asn Pro 100
105 110 Asp Asn Leu Gln Gly Gly Asp Asp Leu
Asp Pro Asn Tyr Val Leu Ser 115 120
125 Ser Arg Val Arg Thr Gly Arg Ser Ile Arg Gly Phe Cys Leu
Pro Pro 130 135 140
His Cys Ser Arg Gly Glu Arg Arg Ala Ile Glu Lys Leu Ala Val Glu 145
150 155 160 Ala Leu Ser Ser Leu
Asp Gly Asp Leu Ala Gly Arg Tyr Tyr Ala Leu 165
170 175 Lys Ser Met Thr Glu Ala Glu Gln Gln Gln
Leu Ile Asp Asp His Phe 180 185
190 Leu Phe Asp Lys Pro Val Ser Pro Leu Leu Leu Ala Ser Gly Met
Ala 195 200 205 Arg
Asp Trp Pro Asp Ala Arg Gly Ile Trp His Asn Asp Asn Lys Thr 210
215 220 Phe Leu Val Trp Val Asn
Glu Glu Asp His Leu Arg Val Ile Ser Met 225 230
235 240 Gln Lys Gly Gly Asn Met Lys Glu Val Phe Thr
Arg Phe Cys Thr Gly 245 250
255 Leu Thr Gln Ile Glu Thr Leu Phe Lys Ser Lys Asp Tyr Glu Phe Met
260 265 270 Trp Asn
Pro His Leu Gly Tyr Ile Leu Thr Cys Pro Ser Asn Leu Gly 275
280 285 Thr Gly Leu Arg Ala Gly Val
His Ile Lys Leu Pro Asn Leu Gly Lys 290 295
300 His Glu Lys Phe Ser Glu Val Leu Lys Arg Leu Arg
Leu Gln Lys Arg 305 310 315
320 Gly Thr Gly Gly Val Asp Thr Ala Ala Val Gly Gly Val Phe Asp Val
325 330 335 Ser Asn Ala
Asp Arg Leu Gly Phe Ser Glu Val Glu Leu Val Gln Met 340
345 350 Val Val Asp Gly Val Lys Leu Leu
Ile Glu Met Glu Gln Arg Leu Glu 355 360
365 Gln Gly Gln Ala Ile Asp Asp Leu Met Pro Ala Gln Lys
370 375 380 90646PRTHomo sapiens
90Met Ser Lys Gly Pro Ala Val Gly Ile Asp Leu Gly Thr Thr Tyr Ser 1
5 10 15 Cys Val Gly Val
Phe Gln His Gly Lys Val Glu Ile Ile Ala Asn Asp 20
25 30 Gln Gly Asn Arg Thr Thr Pro Ser Tyr
Val Ala Phe Thr Asp Thr Glu 35 40
45 Arg Leu Ile Gly Asp Ala Ala Lys Asn Gln Val Ala Met Asn
Pro Thr 50 55 60
Asn Thr Val Phe Asp Ala Lys Arg Leu Ile Gly Arg Arg Phe Asp Asp 65
70 75 80 Ala Val Val Gln Ser
Asp Met Lys His Trp Pro Phe Met Val Val Asn 85
90 95 Asp Ala Gly Arg Pro Lys Val Gln Val Glu
Tyr Lys Gly Glu Thr Lys 100 105
110 Ser Phe Tyr Pro Glu Glu Val Ser Ser Met Val Leu Thr Lys Met
Lys 115 120 125 Glu
Ile Ala Glu Ala Tyr Leu Gly Lys Thr Val Thr Asn Ala Val Val 130
135 140 Thr Val Pro Ala Tyr Phe
Asn Asp Ser Gln Arg Gln Ala Thr Lys Asp 145 150
155 160 Ala Gly Thr Ile Ala Gly Leu Asn Val Leu Arg
Ile Ile Asn Glu Pro 165 170
175 Thr Ala Ala Ala Ile Ala Tyr Gly Leu Asp Lys Lys Val Gly Ala Glu
180 185 190 Arg Asn
Val Leu Ile Phe Asp Leu Gly Gly Gly Thr Phe Asp Val Ser 195
200 205 Ile Leu Thr Ile Glu Asp Gly
Ile Phe Glu Val Lys Ser Thr Ala Gly 210 215
220 Asp Thr His Leu Gly Gly Glu Asp Phe Asp Asn Arg
Met Val Asn His 225 230 235
240 Phe Ile Ala Glu Phe Lys Arg Lys His Lys Lys Asp Ile Ser Glu Asn
245 250 255 Lys Arg Ala
Val Arg Arg Leu Arg Thr Ala Cys Glu Arg Ala Lys Arg 260
265 270 Thr Leu Ser Ser Ser Thr Gln Ala
Ser Ile Glu Ile Asp Ser Leu Tyr 275 280
285 Glu Gly Ile Asp Phe Tyr Thr Ser Ile Thr Arg Ala Arg
Phe Glu Glu 290 295 300
Leu Asn Ala Asp Leu Phe Arg Gly Thr Leu Asp Pro Val Glu Lys Ala 305
310 315 320 Leu Arg Asp Ala
Lys Leu Asp Lys Ser Gln Ile His Asp Ile Val Leu 325
330 335 Val Gly Gly Ser Thr Arg Ile Pro Lys
Ile Gln Lys Leu Leu Gln Asp 340 345
350 Phe Phe Asn Gly Lys Glu Leu Asn Lys Ser Ile Asn Pro Asp
Glu Ala 355 360 365
Val Ala Tyr Gly Ala Ala Val Gln Ala Ala Ile Leu Ser Gly Asp Lys 370
375 380 Ser Glu Asn Val Gln
Asp Leu Leu Leu Leu Asp Val Thr Pro Leu Ser 385 390
395 400 Leu Gly Ile Glu Thr Ala Gly Gly Val Met
Thr Val Leu Ile Lys Arg 405 410
415 Asn Thr Thr Ile Pro Thr Lys Gln Thr Gln Thr Phe Thr Thr Tyr
Ser 420 425 430 Asp
Asn Gln Pro Gly Val Leu Ile Gln Val Tyr Glu Gly Glu Arg Ala 435
440 445 Met Thr Lys Asp Asn Asn
Leu Leu Gly Lys Phe Glu Leu Thr Gly Ile 450 455
460 Pro Pro Ala Pro Arg Gly Val Pro Gln Ile Glu
Val Thr Phe Asp Ile 465 470 475
480 Asp Ala Asn Gly Ile Leu Asn Val Ser Ala Val Asp Lys Ser Thr Gly
485 490 495 Lys Glu
Asn Lys Ile Thr Ile Thr Asn Asp Lys Gly Arg Leu Ser Lys 500
505 510 Glu Asp Ile Glu Arg Met Val
Gln Glu Ala Glu Lys Tyr Lys Ala Glu 515 520
525 Asp Glu Lys Gln Arg Asp Lys Val Ser Ser Lys Asn
Ser Leu Glu Ser 530 535 540
Tyr Ala Phe Asn Met Lys Ala Thr Val Glu Asp Glu Lys Leu Gln Gly 545
550 555 560 Lys Ile Asn
Asp Glu Asp Lys Gln Lys Ile Leu Asp Lys Cys Asn Glu 565
570 575 Ile Ile Asn Trp Leu Asp Lys Asn
Gln Thr Ala Glu Lys Glu Glu Phe 580 585
590 Glu His Gln Gln Lys Glu Leu Glu Lys Val Cys Asn Pro
Ile Ile Thr 595 600 605
Lys Leu Tyr Gln Ser Ala Gly Gly Met Pro Gly Gly Met Pro Gly Gly 610
615 620 Phe Pro Gly Gly
Gly Ala Pro Pro Ser Gly Gly Ala Ser Ser Gly Pro 625 630
635 640 Thr Ile Glu Glu Val Asp
645 91493PRTHomo sapiens 91Met Ser Lys Gly Pro Ala Val Gly Ile
Asp Leu Gly Thr Thr Tyr Ser 1 5 10
15 Cys Val Gly Val Phe Gln His Gly Lys Val Glu Ile Ile Ala
Asn Asp 20 25 30
Gln Gly Asn Arg Thr Thr Pro Ser Tyr Val Ala Phe Thr Asp Thr Glu
35 40 45 Arg Leu Ile Gly
Asp Ala Ala Lys Asn Gln Val Ala Met Asn Pro Thr 50
55 60 Asn Thr Val Phe Asp Ala Lys Arg
Leu Ile Gly Arg Arg Phe Asp Asp 65 70
75 80 Ala Val Val Gln Ser Asp Met Lys His Trp Pro Phe
Met Val Val Asn 85 90
95 Asp Ala Gly Arg Pro Lys Val Gln Val Glu Tyr Lys Gly Glu Thr Lys
100 105 110 Ser Phe Tyr
Pro Glu Glu Val Ser Ser Met Val Leu Thr Lys Met Lys 115
120 125 Glu Ile Ala Glu Ala Tyr Leu Gly
Lys Thr Val Thr Asn Ala Val Val 130 135
140 Thr Val Pro Ala Tyr Phe Asn Asp Ser Gln Arg Gln Ala
Thr Lys Asp 145 150 155
160 Ala Gly Thr Ile Ala Gly Leu Asn Val Leu Arg Ile Ile Asn Glu Pro
165 170 175 Thr Ala Ala Ala
Ile Ala Tyr Gly Leu Asp Lys Lys Val Gly Ala Glu 180
185 190 Arg Asn Val Leu Ile Phe Asp Leu Gly
Gly Gly Thr Phe Asp Val Ser 195 200
205 Ile Leu Thr Ile Glu Asp Gly Ile Phe Glu Val Lys Ser Thr
Ala Gly 210 215 220
Asp Thr His Leu Gly Gly Glu Asp Phe Asp Asn Arg Met Val Asn His 225
230 235 240 Phe Ile Ala Glu Phe
Lys Arg Lys His Lys Lys Asp Ile Ser Glu Asn 245
250 255 Lys Arg Ala Val Arg Arg Leu Arg Thr Ala
Cys Glu Arg Ala Lys Arg 260 265
270 Thr Leu Ser Ser Ser Thr Gln Ala Ser Ile Glu Ile Asp Ser Leu
Tyr 275 280 285 Glu
Gly Ile Asp Phe Tyr Thr Ser Ile Thr Arg Ala Arg Phe Glu Glu 290
295 300 Leu Asn Ala Asp Leu Phe
Arg Gly Thr Leu Asp Pro Val Glu Lys Ala 305 310
315 320 Leu Arg Asp Ala Lys Leu Asp Lys Ser Gln Ile
His Asp Ile Val Leu 325 330
335 Val Gly Gly Ser Thr Arg Ile Pro Lys Ile Gln Lys Leu Leu Gln Asp
340 345 350 Phe Phe
Asn Gly Lys Glu Leu Asn Lys Ser Ile Asn Pro Asp Glu Ala 355
360 365 Val Ala Tyr Gly Ala Ala Val
Gln Ala Ala Ile Leu Ser Gly Asp Lys 370 375
380 Ser Glu Asn Val Gln Asp Leu Leu Leu Leu Asp Val
Thr Pro Leu Ser 385 390 395
400 Leu Gly Ile Glu Thr Ala Gly Gly Val Met Thr Val Leu Ile Lys Arg
405 410 415 Asn Thr Thr
Ile Pro Thr Lys Gln Thr Gln Thr Phe Thr Thr Tyr Ser 420
425 430 Asp Asn Gln Pro Gly Val Leu Ile
Gln Val Tyr Glu Gly Glu Arg Ala 435 440
445 Met Thr Lys Asp Asn Asn Leu Leu Gly Lys Phe Glu Leu
Thr Gly Met 450 455 460
Pro Gly Gly Met Pro Gly Gly Phe Pro Gly Gly Gly Ala Pro Pro Ser 465
470 475 480 Gly Gly Ala Ser
Ser Gly Pro Thr Ile Glu Glu Val Asp 485
490 92679PRTHomo sapiens 92 Met Ile Ser Ala Ser Arg Ala Ala
Ala Ala Arg Leu Val Gly Ala Ala 1 5 10
15 Ala Ser Arg Gly Pro Thr Ala Ala Arg His Gln Asp Ser
Trp Asn Gly 20 25 30
Leu Ser His Glu Ala Phe Arg Leu Val Ser Arg Arg Asp Tyr Ala Ser
35 40 45 Glu Ala Ile Lys
Gly Ala Val Val Gly Ile Asp Leu Gly Thr Thr Asn 50
55 60 Ser Cys Val Ala Val Met Glu Gly
Lys Gln Ala Lys Val Leu Glu Asn 65 70
75 80 Ala Glu Gly Ala Arg Thr Thr Pro Ser Val Val Ala
Phe Thr Ala Asp 85 90
95 Gly Glu Arg Leu Val Gly Met Pro Ala Lys Arg Gln Ala Val Thr Asn
100 105 110 Pro Asn Asn
Thr Phe Tyr Ala Thr Lys Arg Leu Ile Gly Arg Arg Tyr 115
120 125 Asp Asp Pro Glu Val Gln Lys Asp
Ile Lys Asn Val Pro Phe Lys Ile 130 135
140 Val Arg Ala Ser Asn Gly Asp Ala Trp Val Glu Ala His
Gly Lys Leu 145 150 155
160 Tyr Ser Pro Ser Gln Ile Gly Ala Phe Val Leu Met Lys Met Lys Glu
165 170 175 Thr Ala Glu Asn
Tyr Leu Gly His Thr Ala Lys Asn Ala Val Ile Thr 180
185 190 Val Pro Ala Tyr Phe Asn Asp Ser Gln
Arg Gln Ala Thr Lys Asp Ala 195 200
205 Gly Gln Ile Ser Gly Leu Asn Val Leu Arg Val Ile Asn Glu
Pro Thr 210 215 220
Ala Ala Ala Leu Ala Tyr Gly Leu Asp Lys Ser Glu Asp Lys Val Ile 225
230 235 240 Ala Val Tyr Asp Leu
Gly Gly Gly Thr Phe Asp Ile Ser Ile Leu Glu 245
250 255 Ile Gln Lys Gly Val Phe Glu Val Lys Ser
Thr Asn Gly Asp Thr Phe 260 265
270 Leu Gly Gly Glu Asp Phe Asp Gln Ala Leu Leu Arg His Ile Val
Lys 275 280 285 Glu
Phe Lys Arg Glu Thr Gly Val Asp Leu Thr Lys Asp Asn Met Ala 290
295 300 Leu Gln Arg Val Arg Glu
Ala Ala Glu Lys Ala Lys Cys Glu Leu Ser 305 310
315 320 Ser Ser Val Gln Thr Asp Ile Asn Leu Pro Tyr
Leu Thr Met Asp Ser 325 330
335 Ser Gly Pro Lys His Leu Asn Met Lys Leu Thr Arg Ala Gln Phe Glu
340 345 350 Gly Ile
Val Thr Asp Leu Ile Arg Arg Thr Ile Ala Pro Cys Gln Lys 355
360 365 Ala Met Gln Asp Ala Glu Val
Ser Lys Ser Asp Ile Gly Glu Val Ile 370 375
380 Leu Val Gly Gly Met Thr Arg Met Pro Lys Val Gln
Gln Thr Val Gln 385 390 395
400 Asp Leu Phe Gly Arg Ala Pro Ser Lys Ala Val Asn Pro Asp Glu Ala
405 410 415 Val Ala Ile
Gly Ala Ala Ile Gln Gly Gly Val Leu Ala Gly Asp Val 420
425 430 Thr Asp Val Leu Leu Leu Asp Val
Thr Pro Leu Ser Leu Gly Ile Glu 435 440
445 Thr Leu Gly Gly Val Phe Thr Lys Leu Ile Asn Arg Asn
Thr Thr Ile 450 455 460
Pro Thr Lys Lys Ser Gln Val Phe Ser Thr Ala Ala Asp Gly Gln Thr 465
470 475 480 Gln Val Glu Ile
Lys Val Cys Gln Gly Glu Arg Glu Met Ala Gly Asp 485
490 495 Asn Lys Leu Leu Gly Gln Phe Thr Leu
Ile Gly Ile Pro Pro Ala Pro 500 505
510 Arg Gly Val Pro Gln Ile Glu Val Thr Phe Asp Ile Asp Ala
Asn Gly 515 520 525
Ile Val His Val Ser Ala Lys Asp Lys Gly Thr Gly Arg Glu Gln Gln 530
535 540 Ile Val Ile Gln Ser
Ser Gly Gly Leu Ser Lys Asp Asp Ile Glu Asn 545 550
555 560 Met Val Lys Asn Ala Glu Lys Tyr Ala Glu
Glu Asp Arg Arg Lys Lys 565 570
575 Glu Arg Val Glu Ala Val Asn Met Ala Glu Gly Ile Ile His Asp
Thr 580 585 590 Glu
Thr Lys Met Glu Glu Phe Lys Asp Gln Leu Pro Ala Asp Glu Cys 595
600 605 Asn Lys Leu Lys Glu Glu
Ile Ser Lys Met Arg Glu Leu Leu Ala Arg 610 615
620 Lys Asp Ser Glu Thr Gly Glu Asn Ile Arg Gln
Ala Ala Ser Ser Leu 625 630 635
640 Gln Gln Ala Ser Leu Lys Leu Phe Glu Met Ala Tyr Lys Lys Met Ala
645 650 655 Ser Glu
Arg Glu Gly Ser Gly Ser Ser Gly Thr Gly Glu Gln Lys Glu 660
665 670 Asp Gln Lys Glu Glu Lys Gln
675 93505PRTHomo sapiens 93Met Arg Leu Arg Arg
Leu Ala Leu Phe Pro Gly Val Ala Leu Leu Leu 1 5
10 15 Ala Ala Ala Arg Leu Ala Ala Ala Ser Asp
Val Leu Glu Leu Thr Asp 20 25
30 Asp Asn Phe Glu Ser Arg Ile Ser Asp Thr Gly Ser Ala Gly Leu
Met 35 40 45 Leu
Val Glu Phe Phe Ala Pro Trp Cys Gly His Cys Lys Arg Leu Ala 50
55 60 Pro Glu Tyr Glu Ala Ala
Ala Thr Arg Leu Lys Gly Ile Val Pro Leu 65 70
75 80 Ala Lys Val Asp Cys Thr Ala Asn Thr Asn Thr
Cys Asn Lys Tyr Gly 85 90
95 Val Ser Gly Tyr Pro Thr Leu Lys Ile Phe Arg Asp Gly Glu Glu Ala
100 105 110 Gly Ala
Tyr Asp Gly Pro Arg Thr Ala Asp Gly Ile Val Ser His Leu 115
120 125 Lys Lys Gln Ala Gly Pro Ala
Ser Val Pro Leu Arg Thr Glu Glu Glu 130 135
140 Phe Lys Lys Phe Ile Ser Asp Lys Asp Ala Ser Ile
Val Gly Phe Phe 145 150 155
160 Asp Asp Ser Phe Ser Glu Ala His Ser Glu Phe Leu Lys Ala Ala Ser
165 170 175 Asn Leu Arg
Asp Asn Tyr Arg Phe Ala His Thr Asn Val Glu Ser Leu 180
185 190 Val Asn Glu Tyr Asp Asp Asn Gly
Glu Gly Ile Ile Leu Phe Arg Pro 195 200
205 Ser His Leu Thr Asn Lys Phe Glu Asp Lys Thr Val Ala
Tyr Thr Glu 210 215 220
Gln Lys Met Thr Ser Gly Lys Ile Lys Lys Phe Ile Gln Glu Asn Ile 225
230 235 240 Phe Gly Ile Cys
Pro His Met Thr Glu Asp Asn Lys Asp Leu Ile Gln 245
250 255 Gly Lys Asp Leu Leu Ile Ala Tyr Tyr
Asp Val Asp Tyr Glu Lys Asn 260 265
270 Ala Lys Gly Ser Asn Tyr Trp Arg Asn Arg Val Met Met Val
Ala Lys 275 280 285
Lys Phe Leu Asp Ala Gly His Lys Leu Asn Phe Ala Val Ala Ser Arg 290
295 300 Lys Thr Phe Ser His
Glu Leu Ser Asp Phe Gly Leu Glu Ser Thr Ala 305 310
315 320 Gly Glu Ile Pro Val Val Ala Ile Arg Thr
Ala Lys Gly Glu Lys Phe 325 330
335 Val Met Gln Glu Glu Phe Ser Arg Asp Gly Lys Ala Leu Glu Arg
Phe 340 345 350 Leu
Gln Asp Tyr Phe Asp Gly Asn Leu Lys Arg Tyr Leu Lys Ser Glu 355
360 365 Pro Ile Pro Glu Ser Asn
Asp Gly Pro Val Lys Val Val Val Ala Glu 370 375
380 Asn Phe Asp Glu Ile Val Asn Asn Glu Asn Lys
Asp Val Leu Ile Glu 385 390 395
400 Phe Tyr Ala Pro Trp Cys Gly His Cys Lys Asn Leu Glu Pro Lys Tyr
405 410 415 Lys Glu
Leu Gly Glu Lys Leu Ser Lys Asp Pro Asn Ile Val Ile Ala 420
425 430 Lys Met Asp Ala Thr Ala Asn
Asp Val Pro Ser Pro Tyr Glu Val Arg 435 440
445 Gly Phe Pro Thr Ile Tyr Phe Ser Pro Ala Asn Lys
Lys Leu Asn Pro 450 455 460
Lys Lys Tyr Glu Gly Gly Arg Glu Leu Ser Asp Phe Ile Ser Tyr Leu 465
470 475 480 Gln Arg Glu
Ala Thr Asn Pro Pro Val Ile Gln Glu Glu Lys Pro Lys 485
490 495 Lys Lys Lys Lys Ala Gln Glu Asp
Leu 500 505 94617PRTHomo sapiens 94Met Asp
Phe Ser Lys Leu Pro Lys Ile Leu Asp Glu Asp Lys Glu Ser 1 5
10 15 Thr Phe Gly Tyr Val His Gly
Val Ser Gly Pro Val Val Thr Ala Cys 20 25
30 Asp Met Ala Gly Ala Ala Met Tyr Glu Leu Val Arg
Val Gly His Ser 35 40 45
Glu Leu Val Gly Glu Ile Ile Arg Leu Glu Gly Asp Met Ala Thr Ile
50 55 60 Gln Val Tyr
Glu Glu Thr Ser Gly Val Ser Val Gly Asp Pro Val Leu 65
70 75 80 Arg Thr Gly Lys Pro Leu Ser
Val Glu Leu Gly Pro Gly Ile Met Gly 85
90 95 Ala Ile Phe Asp Gly Ile Gln Arg Pro Leu Ser
Asp Ile Ser Ser Gln 100 105
110 Thr Gln Ser Ile Tyr Ile Pro Arg Gly Val Asn Val Ser Ala Leu
Ser 115 120 125 Arg
Asp Ile Lys Trp Asp Phe Thr Pro Cys Lys Asn Leu Arg Val Gly 130
135 140 Ser His Ile Thr Gly Gly
Asp Ile Tyr Gly Ile Val Ser Glu Asn Ser 145 150
155 160 Leu Ile Lys His Lys Ile Met Leu Pro Pro Arg
Asn Arg Gly Thr Val 165 170
175 Thr Tyr Ile Ala Pro Pro Gly Asn Tyr Asp Thr Ser Asp Val Val Leu
180 185 190 Glu Leu
Glu Phe Glu Gly Val Lys Glu Lys Phe Thr Met Val Gln Val 195
200 205 Trp Pro Val Arg Gln Val Arg
Pro Val Thr Glu Lys Leu Pro Ala Asn 210 215
220 His Pro Leu Leu Thr Gly Gln Arg Val Leu Asp Ala
Leu Phe Pro Cys 225 230 235
240 Val Gln Gly Gly Thr Thr Ala Ile Pro Gly Ala Phe Gly Cys Gly Lys
245 250 255 Thr Val Ile
Ser Gln Ser Leu Ser Lys Tyr Ser Asn Ser Asp Val Ile 260
265 270 Ile Tyr Val Gly Cys Gly Glu Arg
Gly Asn Glu Met Ser Glu Val Leu 275 280
285 Arg Asp Phe Pro Glu Leu Thr Met Glu Val Asp Gly Lys
Val Glu Ser 290 295 300
Ile Met Lys Arg Thr Ala Leu Val Ala Asn Thr Ser Asn Met Pro Val 305
310 315 320 Ala Ala Arg Glu
Ala Ser Ile Tyr Thr Gly Ile Thr Leu Ser Glu Tyr 325
330 335 Phe Arg Asp Met Gly Tyr His Val Ser
Met Met Ala Asp Ser Thr Ser 340 345
350 Arg Trp Ala Glu Ala Leu Arg Glu Ile Ser Gly Arg Leu Ala
Glu Met 355 360 365
Pro Ala Asp Ser Gly Tyr Pro Ala Tyr Leu Gly Ala Arg Leu Ala Ser 370
375 380 Phe Tyr Glu Arg Ala
Gly Arg Val Lys Cys Leu Gly Asn Pro Glu Arg 385 390
395 400 Glu Gly Ser Val Ser Ile Val Gly Ala Val
Ser Pro Pro Gly Gly Asp 405 410
415 Phe Ser Asp Pro Val Thr Ser Ala Thr Leu Gly Ile Val Gln Val
Phe 420 425 430 Trp
Gly Leu Asp Lys Lys Leu Ala Gln Arg Lys His Phe Pro Ser Val 435
440 445 Asn Trp Leu Ile Ser Tyr
Ser Lys Tyr Met Arg Ala Leu Asp Glu Tyr 450 455
460 Tyr Asp Lys His Phe Thr Glu Phe Val Pro Leu
Arg Thr Lys Ala Lys 465 470 475
480 Glu Ile Leu Gln Glu Glu Glu Asp Leu Ala Glu Ile Val Gln Leu Val
485 490 495 Gly Lys
Ala Ser Leu Ala Glu Thr Asp Lys Ile Thr Leu Glu Val Ala 500
505 510 Lys Leu Ile Lys Asp Asp Phe
Leu Gln Gln Asn Gly Tyr Thr Pro Tyr 515 520
525 Asp Arg Phe Cys Pro Phe Tyr Lys Thr Val Gly Met
Leu Ser Asn Met 530 535 540
Ile Ala Phe Tyr Asp Met Ala Arg Arg Ala Val Glu Thr Thr Ala Gln 545
550 555 560 Ser Asp Asn
Lys Ile Thr Trp Ser Ile Ile Arg Glu His Met Gly Asp 565
570 575 Ile Leu Tyr Lys Leu Ser Ser Met
Lys Phe Lys Asp Pro Leu Lys Asp 580 585
590 Gly Glu Ala Lys Ile Lys Ser Asp Tyr Ala Gln Leu Leu
Glu Asp Met 595 600 605
Gln Asn Ala Phe Arg Ser Leu Glu Asp 610 615
95418PRTHomo sapiens 95Met Glu Glu Ile Gly Ile Leu Val Glu Lys Ala Gln
Asp Glu Ile Pro 1 5 10
15 Ala Leu Ser Val Ser Arg Pro Gln Thr Gly Leu Ser Phe Leu Gly Pro
20 25 30 Glu Pro Glu
Asp Leu Glu Asp Leu Tyr Ser Arg Tyr Lys Lys Leu Gln 35
40 45 Gln Glu Leu Glu Phe Leu Glu Val
Gln Glu Glu Tyr Ile Lys Asp Glu 50 55
60 Gln Lys Asn Leu Lys Lys Glu Phe Leu His Ala Gln Glu
Glu Val Lys 65 70 75
80 Arg Ile Gln Ser Ile Pro Leu Val Ile Gly Gln Phe Leu Glu Ala Val
85 90 95 Asp Gln Asn Thr
Ala Ile Val Gly Ser Thr Thr Gly Ser Asn Tyr Tyr 100
105 110 Val Arg Ile Leu Ser Thr Ile Asp Arg
Glu Leu Leu Lys Pro Asn Ala 115 120
125 Ser Val Ala Leu His Lys His Ser Asn Ala Leu Val Asp Val
Leu Pro 130 135 140
Pro Glu Ala Asp Ser Ser Ile Met Met Leu Thr Ser Asp Gln Lys Pro 145
150 155 160 Asp Val Met Tyr Ala
Asp Ile Gly Gly Met Asp Ile Gln Lys Gln Glu 165
170 175 Val Arg Glu Ala Val Glu Leu Pro Leu Thr
His Phe Glu Leu Tyr Lys 180 185
190 Gln Ile Gly Ile Asp Pro Pro Arg Gly Val Leu Met Tyr Gly Pro
Pro 195 200 205 Gly
Cys Gly Lys Thr Met Leu Ala Lys Ala Val Ala His His Thr Thr 210
215 220 Ala Ala Phe Ile Arg Val
Val Gly Ser Glu Phe Val Gln Lys Tyr Leu 225 230
235 240 Gly Glu Gly Pro Arg Met Val Arg Asp Val Phe
Arg Leu Ala Lys Glu 245 250
255 Asn Ala Pro Ala Ile Ile Phe Ile Asp Glu Ile Asp Ala Ile Ala Thr
260 265 270 Lys Arg
Phe Asp Ala Gln Thr Gly Ala Asp Arg Glu Val Gln Arg Ile 275
280 285 Leu Leu Glu Leu Leu Asn Gln
Met Asp Gly Phe Asp Gln Asn Val Asn 290 295
300 Val Lys Val Ile Met Ala Thr Asn Arg Ala Asp Thr
Leu Asp Pro Ala 305 310 315
320 Leu Leu Arg Pro Gly Arg Leu Asp Arg Lys Ile Glu Phe Pro Leu Pro
325 330 335 Asp Arg Arg
Gln Lys Arg Leu Ile Phe Ser Thr Ile Thr Ser Lys Met 340
345 350 Asn Leu Ser Glu Glu Val Asp Leu
Glu Asp Tyr Val Ala Arg Pro Asp 355 360
365 Lys Ile Ser Gly Ala Asp Ile Asn Ser Ile Cys Gln Glu
Ser Gly Met 370 375 380
Leu Ala Val Arg Glu Asn Arg Tyr Ile Val Leu Ala Lys Asp Phe Glu 385
390 395 400 Lys Ala Tyr Lys
Thr Val Ile Lys Lys Asp Glu Gln Glu His Glu Phe 405
410 415 Tyr Lys 96387PRTHomo sapiens 96Met
Glu Glu Ile Gly Ile Leu Val Glu Lys Ala Gln Asp Glu Ile Pro 1
5 10 15 Ala Leu Ser Val Ser Arg
Pro Gln Thr Gly Leu Ser Phe Leu Gly Pro 20
25 30 Glu Pro Glu Asp Leu Glu Asp Leu Tyr Ser
Arg Tyr Lys Glu Glu Val 35 40
45 Lys Arg Ile Gln Ser Ile Pro Leu Val Ile Gly Gln Phe Leu
Glu Ala 50 55 60
Val Asp Gln Asn Thr Ala Ile Val Gly Ser Thr Thr Gly Ser Asn Tyr 65
70 75 80 Tyr Val Arg Ile Leu
Ser Thr Ile Asp Arg Glu Leu Leu Lys Pro Asn 85
90 95 Ala Ser Val Ala Leu His Lys His Ser Asn
Ala Leu Val Asp Val Leu 100 105
110 Pro Pro Glu Ala Asp Ser Ser Ile Met Met Leu Thr Ser Asp Gln
Lys 115 120 125 Pro
Asp Val Met Tyr Ala Asp Ile Gly Gly Met Asp Ile Gln Lys Gln 130
135 140 Glu Val Arg Glu Ala Val
Glu Leu Pro Leu Thr His Phe Glu Leu Tyr 145 150
155 160 Lys Gln Ile Gly Ile Asp Pro Pro Arg Gly Val
Leu Met Tyr Gly Pro 165 170
175 Pro Gly Cys Gly Lys Thr Met Leu Ala Lys Ala Val Ala His His Thr
180 185 190 Thr Ala
Ala Phe Ile Arg Val Val Gly Ser Glu Phe Val Gln Lys Tyr 195
200 205 Leu Gly Glu Gly Pro Arg Met
Val Arg Asp Val Phe Arg Leu Ala Lys 210 215
220 Glu Asn Ala Pro Ala Ile Ile Phe Ile Asp Glu Ile
Asp Ala Ile Ala 225 230 235
240 Thr Lys Arg Phe Asp Ala Gln Thr Gly Ala Asp Arg Glu Val Gln Arg
245 250 255 Ile Leu Leu
Glu Leu Leu Asn Gln Met Asp Gly Phe Asp Gln Asn Val 260
265 270 Asn Val Lys Val Ile Met Ala Thr
Asn Arg Ala Asp Thr Leu Asp Pro 275 280
285 Ala Leu Leu Arg Pro Gly Arg Leu Asp Arg Lys Ile Glu
Phe Pro Leu 290 295 300
Pro Asp Arg Arg Gln Lys Arg Leu Ile Phe Ser Thr Ile Thr Ser Lys 305
310 315 320 Met Asn Leu Ser
Glu Glu Val Asp Leu Glu Asp Tyr Val Ala Arg Pro 325
330 335 Asp Lys Ile Ser Gly Ala Asp Ile Asn
Ser Ile Cys Gln Glu Ser Gly 340 345
350 Met Leu Ala Val Arg Glu Asn Arg Tyr Ile Val Leu Ala Lys
Asp Phe 355 360 365
Glu Lys Ala Tyr Lys Thr Val Ile Lys Lys Asp Glu Gln Glu His Glu 370
375 380 Phe Tyr Lys 385
97234PRTHomo sapiens 97Met Ala Glu Arg Gly Tyr Ser Phe Ser Leu Thr
Thr Phe Ser Pro Ser 1 5 10
15 Gly Lys Leu Val Gln Ile Glu Tyr Ala Leu Ala Ala Val Ala Gly Gly
20 25 30 Ala Pro
Ser Val Gly Ile Lys Ala Ala Asn Gly Val Val Leu Ala Thr 35
40 45 Glu Lys Lys Gln Lys Ser Ile
Leu Tyr Asp Glu Arg Ser Val His Lys 50 55
60 Val Glu Pro Ile Thr Lys His Ile Gly Leu Val Tyr
Ser Gly Met Gly 65 70 75
80 Pro Asp Tyr Arg Val Leu Val His Arg Ala Arg Lys Leu Ala Gln Gln
85 90 95 Tyr Tyr Leu
Val Tyr Gln Glu Pro Ile Pro Thr Ala Gln Leu Val Gln 100
105 110 Arg Val Ala Ser Val Met Gln Glu
Tyr Thr Gln Ser Gly Gly Val Arg 115 120
125 Pro Phe Gly Val Ser Leu Leu Ile Cys Gly Trp Asn Glu
Gly Arg Pro 130 135 140
Tyr Leu Phe Gln Ser Asp Pro Ser Gly Ala Tyr Phe Ala Trp Lys Ala 145
150 155 160 Thr Ala Met Gly
Lys Asn Tyr Val Asn Gly Lys Thr Phe Leu Glu Lys 165
170 175 Arg Tyr Asn Glu Asp Leu Glu Leu Glu
Asp Ala Ile His Thr Ala Ile 180 185
190 Leu Thr Leu Lys Glu Ser Phe Glu Gly Gln Met Thr Glu Asp
Asn Ile 195 200 205
Glu Val Gly Ile Cys Asn Glu Ala Gly Phe Arg Arg Leu Thr Pro Thr 210
215 220 Glu Val Lys Asp Tyr
Leu Ala Ala Ile Ala 225 230 98223PRTHomo
sapiens 98Met Gln Leu Lys Pro Met Glu Ile Asn Pro Glu Met Leu Asn Lys Val
1 5 10 15 Leu Ser
Arg Leu Gly Val Ala Gly Gln Trp Arg Phe Val Asp Val Leu 20
25 30 Gly Leu Glu Glu Glu Ser Leu
Gly Ser Val Pro Ala Pro Ala Cys Ala 35 40
45 Leu Leu Leu Leu Phe Pro Leu Thr Ala Gln His Glu
Asn Phe Arg Lys 50 55 60
Lys Gln Ile Glu Glu Leu Lys Gly Gln Glu Val Ser Pro Lys Val Tyr 65
70 75 80 Phe Met Lys
Gln Thr Ile Gly Asn Ser Cys Gly Thr Ile Gly Leu Ile 85
90 95 His Ala Val Ala Asn Asn Gln Asp
Lys Leu Gly Phe Glu Asp Gly Ser 100 105
110 Val Leu Lys Gln Phe Leu Ser Glu Thr Glu Lys Met Ser
Pro Glu Asp 115 120 125
Arg Ala Lys Cys Phe Glu Lys Asn Glu Ala Ile Gln Ala Ala His Asp 130
135 140 Ala Val Ala Gln
Glu Gly Gln Cys Arg Val Asp Asp Lys Val Asn Phe 145 150
155 160 His Phe Ile Leu Phe Asn Asn Val Asp
Gly His Leu Tyr Glu Leu Asp 165 170
175 Gly Arg Met Pro Phe Pro Val Asn His Gly Ala Ser Ser Glu
Asp Thr 180 185 190
Leu Leu Lys Asp Ala Ala Lys Val Cys Arg Glu Phe Thr Glu Arg Glu
195 200 205 Gln Gly Glu Val
Arg Phe Ser Ala Val Ala Leu Cys Lys Ala Ala 210 215
220 99806PRTHomo sapiens 99Met Ala Ser Gly Ala
Asp Ser Lys Gly Asp Asp Leu Ser Thr Ala Ile 1 5
10 15 Leu Lys Gln Lys Asn Arg Pro Asn Arg Leu
Ile Val Asp Glu Ala Ile 20 25
30 Asn Glu Asp Asn Ser Val Val Ser Leu Ser Gln Pro Lys Met Asp
Glu 35 40 45 Leu
Gln Leu Phe Arg Gly Asp Thr Val Leu Leu Lys Gly Lys Lys Arg 50
55 60 Arg Glu Ala Val Cys Ile
Val Leu Ser Asp Asp Thr Cys Ser Asp Glu 65 70
75 80 Lys Ile Arg Met Asn Arg Val Val Arg Asn Asn
Leu Arg Val Arg Leu 85 90
95 Gly Asp Val Ile Ser Ile Gln Pro Cys Pro Asp Val Lys Tyr Gly Lys
100 105 110 Arg Ile
His Val Leu Pro Ile Asp Asp Thr Val Glu Gly Ile Thr Gly 115
120 125 Asn Leu Phe Glu Val Tyr Leu
Lys Pro Tyr Phe Leu Glu Ala Tyr Arg 130 135
140 Pro Ile Arg Lys Gly Asp Ile Phe Leu Val Arg Gly
Gly Met Arg Ala 145 150 155
160 Val Glu Phe Lys Val Val Glu Thr Asp Pro Ser Pro Tyr Cys Ile Val
165 170 175 Ala Pro Asp
Thr Val Ile His Cys Glu Gly Glu Pro Ile Lys Arg Glu 180
185 190 Asp Glu Glu Glu Ser Leu Asn Glu
Val Gly Tyr Asp Asp Ile Gly Gly 195 200
205 Cys Arg Lys Gln Leu Ala Gln Ile Lys Glu Met Val Glu
Leu Pro Leu 210 215 220
Arg His Pro Ala Leu Phe Lys Ala Ile Gly Val Lys Pro Pro Arg Gly 225
230 235 240 Ile Leu Leu Tyr
Gly Pro Pro Gly Thr Gly Lys Thr Leu Ile Ala Arg 245
250 255 Ala Val Ala Asn Glu Thr Gly Ala Phe
Phe Phe Leu Ile Asn Gly Pro 260 265
270 Glu Ile Met Ser Lys Leu Ala Gly Glu Ser Glu Ser Asn Leu
Arg Lys 275 280 285
Ala Phe Glu Glu Ala Glu Lys Asn Ala Pro Ala Ile Ile Phe Ile Asp 290
295 300 Glu Leu Asp Ala Ile
Ala Pro Lys Arg Glu Lys Thr His Gly Glu Val 305 310
315 320 Glu Arg Arg Ile Val Ser Gln Leu Leu Thr
Leu Met Asp Gly Leu Lys 325 330
335 Gln Arg Ala His Val Ile Val Met Ala Ala Thr Asn Arg Pro Asn
Ser 340 345 350 Ile
Asp Pro Ala Leu Arg Arg Phe Gly Arg Phe Asp Arg Glu Val Asp 355
360 365 Ile Gly Ile Pro Asp Ala
Thr Gly Arg Leu Glu Ile Leu Gln Ile His 370 375
380 Thr Lys Asn Met Lys Leu Ala Asp Asp Val Asp
Leu Glu Gln Val Ala 385 390 395
400 Asn Glu Thr His Gly His Val Gly Ala Asp Leu Ala Ala Leu Cys Ser
405 410 415 Glu Ala
Ala Leu Gln Ala Ile Arg Lys Lys Met Asp Leu Ile Asp Leu 420
425 430 Glu Asp Glu Thr Ile Asp Ala
Glu Val Met Asn Ser Leu Ala Val Thr 435 440
445 Met Asp Asp Phe Arg Trp Ala Leu Ser Gln Ser Asn
Pro Ser Ala Leu 450 455 460
Arg Glu Thr Val Val Glu Val Pro Gln Val Thr Trp Glu Asp Ile Gly 465
470 475 480 Gly Leu Glu
Asp Val Lys Arg Glu Leu Gln Glu Leu Val Gln Tyr Pro 485
490 495 Val Glu His Pro Asp Lys Phe Leu
Lys Phe Gly Met Thr Pro Ser Lys 500 505
510 Gly Val Leu Phe Tyr Gly Pro Pro Gly Cys Gly Lys Thr
Leu Leu Ala 515 520 525
Lys Ala Ile Ala Asn Glu Cys Gln Ala Asn Phe Ile Ser Ile Lys Gly 530
535 540 Pro Glu Leu Leu
Thr Met Trp Phe Gly Glu Ser Glu Ala Asn Val Arg 545 550
555 560 Glu Ile Phe Asp Lys Ala Arg Gln Ala
Ala Pro Cys Val Leu Phe Phe 565 570
575 Asp Glu Leu Asp Ser Ile Ala Lys Ala Arg Gly Gly Asn Ile
Gly Asp 580 585 590
Gly Gly Gly Ala Ala Asp Arg Val Ile Asn Gln Ile Leu Thr Glu Met
595 600 605 Asp Gly Met Ser
Thr Lys Lys Asn Val Phe Ile Ile Gly Ala Thr Asn 610
615 620 Arg Pro Asp Ile Ile Asp Pro Ala
Ile Leu Arg Pro Gly Arg Leu Asp 625 630
635 640 Gln Leu Ile Tyr Ile Pro Leu Pro Asp Glu Lys Ser
Arg Val Ala Ile 645 650
655 Leu Lys Ala Asn Leu Arg Lys Ser Pro Val Ala Lys Asp Val Asp Leu
660 665 670 Glu Phe Leu
Ala Lys Met Thr Asn Gly Phe Ser Gly Ala Asp Leu Thr 675
680 685 Glu Ile Cys Gln Arg Ala Cys Lys
Leu Ala Ile Arg Glu Ser Ile Glu 690 695
700 Ser Glu Ile Arg Arg Glu Arg Glu Arg Gln Thr Asn Pro
Ser Ala Met 705 710 715
720 Glu Val Glu Glu Asp Asp Pro Val Pro Glu Ile Arg Arg Asp His Phe
725 730 735 Glu Glu Ala Met
Arg Phe Ala Arg Arg Ser Val Ser Asp Asn Asp Ile 740
745 750 Arg Lys Tyr Glu Met Phe Ala Gln Thr
Leu Gln Gln Ser Arg Gly Phe 755 760
765 Gly Ser Phe Arg Phe Pro Ser Gly Asn Gln Gly Gly Ala Gly
Pro Ser 770 775 780
Gln Gly Ser Gly Gly Gly Thr Gly Gly Ser Val Tyr Thr Glu Asp Asn 785
790 795 800 Asp Asp Asp Leu Tyr
Gly 805 100336PRTHomo sapiens 100Met Ala Ala Ser Leu
Arg Leu Leu Gly Ala Ala Ser Gly Leu Arg Tyr 1 5
10 15 Trp Ser Arg Arg Leu Arg Pro Ala Ala Gly
Ser Phe Ala Ala Val Cys 20 25
30 Ser Arg Ser Val Ala Ser Lys Thr Pro Val Gly Phe Ile Gly Leu
Gly 35 40 45 Asn
Met Gly Asn Pro Met Ala Lys Asn Leu Met Lys His Gly Tyr Pro 50
55 60 Leu Ile Ile Tyr Asp Val
Phe Pro Asp Ala Cys Lys Glu Phe Gln Asp 65 70
75 80 Ala Gly Glu Gln Val Val Ser Ser Pro Ala Asp
Val Ala Glu Lys Ala 85 90
95 Asp Arg Ile Ile Thr Met Leu Pro Thr Ser Ile Asn Ala Ile Glu Ala
100 105 110 Tyr Ser
Gly Ala Asn Gly Ile Leu Lys Lys Val Lys Lys Gly Ser Leu 115
120 125 Leu Ile Asp Ser Ser Thr Ile
Asp Pro Ala Val Ser Lys Glu Leu Ala 130 135
140 Lys Glu Val Glu Lys Met Gly Ala Val Phe Met Asp
Ala Pro Val Ser 145 150 155
160 Gly Gly Val Gly Ala Ala Arg Ser Gly Asn Leu Thr Phe Met Val Gly
165 170 175 Gly Val Glu
Asp Glu Phe Ala Ala Ala Gln Glu Leu Leu Gly Cys Met 180
185 190 Gly Ser Asn Val Val Tyr Cys Gly
Ala Val Gly Thr Gly Gln Ala Ala 195 200
205 Lys Ile Cys Asn Asn Met Leu Leu Ala Ile Ser Met Ile
Gly Thr Ala 210 215 220
Glu Ala Met Asn Leu Gly Ile Arg Leu Gly Leu Asp Pro Lys Leu Leu 225
230 235 240 Ala Lys Ile Leu
Asn Met Ser Ser Gly Arg Cys Trp Ser Ser Asp Thr 245
250 255 Tyr Asn Pro Val Pro Gly Val Met Asp
Gly Val Pro Ser Ala Asn Asn 260 265
270 Tyr Gln Gly Gly Phe Gly Thr Thr Leu Met Ala Lys Asp Leu
Gly Leu 275 280 285
Ala Gln Asp Ser Ala Thr Ser Thr Lys Ser Pro Ile Leu Leu Gly Ser 290
295 300 Leu Ala His Gln Ile
Tyr Arg Met Met Cys Ala Lys Gly Tyr Ser Lys 305 310
315 320 Lys Asp Phe Ser Ser Val Phe Gln Phe Leu
Arg Glu Glu Glu Thr Phe 325 330
335 101291PRTHomo sapiens 101 Met Val Ala Val Leu Gly Gly Arg
Gly Val Leu Arg Leu Arg Leu Leu 1 5 10
15 Leu Ser Ala Leu Lys Pro Gly Ile His Val Pro Arg Ala
Gly Pro Ala 20 25 30
Ala Ala Phe Gly Thr Ser Val Thr Ser Ala Lys Val Ala Val Asn Gly
35 40 45 Val Gln Leu His
Tyr Gln Gln Thr Gly Glu Gly Asp His Ala Val Leu 50
55 60 Leu Leu Pro Gly Met Leu Gly Ser
Gly Glu Thr Asp Phe Gly Pro Gln 65 70
75 80 Leu Lys Asn Leu Asn Lys Lys Leu Phe Thr Val Val
Ala Trp Asp Pro 85 90
95 Arg Gly Tyr Gly His Ser Arg Pro Pro Asp Arg Asp Phe Pro Ala Asp
100 105 110 Phe Phe Glu
Arg Asp Ala Lys Asp Ala Val Asp Leu Met Lys Ala Leu 115
120 125 Lys Phe Lys Lys Val Ser Leu Leu
Gly Trp Ser Asp Gly Gly Ile Thr 130 135
140 Ala Leu Ile Ala Ala Ala Lys Tyr Pro Ser Tyr Ile His
Lys Met Val 145 150 155
160 Ile Trp Gly Ala Asn Ala Tyr Val Thr Asp Glu Asp Ser Met Ile Tyr
165 170 175 Glu Gly Ile Arg
Asp Val Ser Lys Trp Ser Glu Arg Thr Arg Lys Pro 180
185 190 Leu Glu Ala Leu Tyr Gly Tyr Asp Tyr
Phe Ala Arg Thr Cys Glu Lys 195 200
205 Trp Val Asp Gly Ile Arg Gln Phe Lys His Leu Pro Asp Gly
Asn Ile 210 215 220
Cys Arg His Leu Leu Pro Arg Val Gln Cys Pro Ala Leu Ile Val His 225
230 235 240 Gly Glu Lys Asp Pro
Leu Val Pro Arg Phe His Ala Asp Phe Ile His 245
250 255 Lys His Val Lys Gly Ser Arg Leu His Leu
Met Pro Glu Gly Lys His 260 265
270 Asn Leu His Leu Arg Phe Ala Asp Glu Phe Asn Lys Leu Ala Glu
Asp 275 280 285 Phe
Leu Gln 290 102259PRTHomo sapiens 102Met Ala Ala Cys Arg Ala Leu
Lys Ala Val Leu Val Asp Leu Ser Gly 1 5
10 15 Thr Leu His Ile Glu Asp Ala Ala Val Pro Gly
Ala Gln Glu Ala Leu 20 25
30 Lys Arg Leu Arg Gly Ala Ser Val Ile Ile Arg Phe Val Thr Asn
Thr 35 40 45 Thr
Lys Glu Ser Lys Gln Asp Leu Leu Glu Arg Leu Arg Lys Leu Glu 50
55 60 Phe Asp Ile Ser Glu Asp
Glu Ile Phe Thr Ser Leu Thr Ala Ala Arg 65 70
75 80 Ser Leu Leu Glu Arg Lys Gln Val Arg Pro Met
Leu Leu Val Asp Asp 85 90
95 Arg Ala Leu Pro Asp Phe Lys Gly Ile Gln Thr Ser Asp Pro Asn Ala
100 105 110 Val Val
Met Gly Leu Ala Pro Glu His Phe His Tyr Gln Ile Leu Asn 115
120 125 Gln Ala Phe Arg Leu Leu Leu
Asp Gly Ala Pro Leu Ile Ala Ile His 130 135
140 Lys Ala Arg Tyr Tyr Lys Arg Lys Asp Gly Leu Ala
Leu Gly Pro Gly 145 150 155
160 Pro Phe Val Thr Ala Leu Glu Tyr Ala Thr Asp Thr Lys Ala Thr Val
165 170 175 Val Gly Lys
Pro Glu Lys Thr Phe Phe Leu Glu Ala Leu Arg Gly Thr 180
185 190 Gly Cys Glu Pro Glu Glu Ala Val
Met Ile Gly Asp Asp Cys Arg Asp 195 200
205 Asp Val Gly Gly Ala Gln Asp Val Gly Met Leu Gly Ile
Leu Val Lys 210 215 220
Thr Gly Lys Tyr Arg Ala Ser Asp Glu Glu Lys Ile Asn Pro Pro Pro 225
230 235 240 Tyr Leu Thr Cys
Glu Ser Phe Pro His Ala Val Asp His Ile Leu Gln 245
250 255 His Leu Leu 103375PRTHomo sapiens
103Met Asp Asp Asp Ile Ala Ala Leu Val Val Asp Asn Gly Ser Gly Met 1
5 10 15 Cys Lys Ala Gly
Phe Ala Gly Asp Asp Ala Pro Arg Ala Val Phe Pro 20
25 30 Ser Ile Val Gly Arg Pro Arg His Gln
Gly Val Met Val Gly Met Gly 35 40
45 Gln Lys Asp Ser Tyr Val Gly Asp Glu Ala Gln Ser Lys Arg
Gly Ile 50 55 60
Leu Thr Leu Lys Tyr Pro Ile Glu His Gly Ile Val Thr Asn Trp Asp 65
70 75 80 Asp Met Glu Lys Ile
Trp His His Thr Phe Tyr Asn Glu Leu Arg Val 85
90 95 Ala Pro Glu Glu His Pro Val Leu Leu Thr
Glu Ala Pro Leu Asn Pro 100 105
110 Lys Ala Asn Arg Glu Lys Met Thr Gln Ile Met Phe Glu Thr Phe
Asn 115 120 125 Thr
Pro Ala Met Tyr Val Ala Ile Gln Ala Val Leu Ser Leu Tyr Ala 130
135 140 Ser Gly Arg Thr Thr Gly
Ile Val Met Asp Ser Gly Asp Gly Val Thr 145 150
155 160 His Thr Val Pro Ile Tyr Glu Gly Tyr Ala Leu
Pro His Ala Ile Leu 165 170
175 Arg Leu Asp Leu Ala Gly Arg Asp Leu Thr Asp Tyr Leu Met Lys Ile
180 185 190 Leu Thr
Glu Arg Gly Tyr Ser Phe Thr Thr Thr Ala Glu Arg Glu Ile 195
200 205 Val Arg Asp Ile Lys Glu Lys
Leu Cys Tyr Val Ala Leu Asp Phe Glu 210 215
220 Gln Glu Met Ala Thr Ala Ala Ser Ser Ser Ser Leu
Glu Lys Ser Tyr 225 230 235
240 Glu Leu Pro Asp Gly Gln Val Ile Thr Ile Gly Asn Glu Arg Phe Arg
245 250 255 Cys Pro Glu
Ala Leu Phe Gln Pro Ser Phe Leu Gly Met Glu Ser Cys 260
265 270 Gly Ile His Glu Thr Thr Phe Asn
Ser Ile Met Lys Cys Asp Val Asp 275 280
285 Ile Arg Lys Asp Leu Tyr Ala Asn Thr Val Leu Ser Gly
Gly Thr Thr 290 295 300
Met Tyr Pro Gly Ile Ala Asp Arg Met Gln Lys Glu Ile Thr Ala Leu 305
310 315 320 Ala Pro Ser Thr
Met Lys Ile Lys Ile Ile Ala Pro Pro Glu Arg Lys 325
330 335 Tyr Ser Val Trp Ile Gly Gly Ser Ile
Leu Ala Ser Leu Ser Thr Phe 340 345
350 Gln Gln Met Trp Ile Ser Lys Gln Glu Tyr Asp Glu Ser Gly
Pro Ser 355 360 365
Ile Val His Arg Lys Cys Phe 370 375 104375PRTHomo
sapiens 104Met Glu Glu Glu Ile Ala Ala Leu Val Ile Asp Asn Gly Ser Gly
Met 1 5 10 15 Cys
Lys Ala Gly Phe Ala Gly Asp Asp Ala Pro Arg Ala Val Phe Pro
20 25 30 Ser Ile Val Gly Arg
Pro Arg His Gln Gly Val Met Val Gly Met Gly 35
40 45 Gln Lys Asp Ser Tyr Val Gly Asp Glu
Ala Gln Ser Lys Arg Gly Ile 50 55
60 Leu Thr Leu Lys Tyr Pro Ile Glu His Gly Ile Val Thr
Asn Trp Asp 65 70 75
80 Asp Met Glu Lys Ile Trp His His Thr Phe Tyr Asn Glu Leu Arg Val
85 90 95 Ala Pro Glu Glu
His Pro Val Leu Leu Thr Glu Ala Pro Leu Asn Pro 100
105 110 Lys Ala Asn Arg Glu Lys Met Thr Gln
Ile Met Phe Glu Thr Phe Asn 115 120
125 Thr Pro Ala Met Tyr Val Ala Ile Gln Ala Val Leu Ser Leu
Tyr Ala 130 135 140
Ser Gly Arg Thr Thr Gly Ile Val Met Asp Ser Gly Asp Gly Val Thr 145
150 155 160 His Thr Val Pro Ile
Tyr Glu Gly Tyr Ala Leu Pro His Ala Ile Leu 165
170 175 Arg Leu Asp Leu Ala Gly Arg Asp Leu Thr
Asp Tyr Leu Met Lys Ile 180 185
190 Leu Thr Glu Arg Gly Tyr Ser Phe Thr Thr Thr Ala Glu Arg Glu
Ile 195 200 205 Val
Arg Asp Ile Lys Glu Lys Leu Cys Tyr Val Ala Leu Asp Phe Glu 210
215 220 Gln Glu Met Ala Thr Ala
Ala Ser Ser Ser Ser Leu Glu Lys Ser Tyr 225 230
235 240 Glu Leu Pro Asp Gly Gln Val Ile Thr Ile Gly
Asn Glu Arg Phe Arg 245 250
255 Cys Pro Glu Ala Leu Phe Gln Pro Ser Phe Leu Gly Met Glu Ser Cys
260 265 270 Gly Ile
His Glu Thr Thr Phe Asn Ser Ile Met Lys Cys Asp Val Asp 275
280 285 Ile Arg Lys Asp Leu Tyr Ala
Asn Thr Val Leu Ser Gly Gly Thr Thr 290 295
300 Met Tyr Pro Gly Ile Ala Asp Arg Met Gln Lys Glu
Ile Thr Ala Leu 305 310 315
320 Ala Pro Ser Thr Met Lys Ile Lys Ile Ile Ala Pro Pro Glu Arg Lys
325 330 335 Tyr Ser Val
Trp Ile Gly Gly Ser Ile Leu Ala Ser Leu Ser Thr Phe 340
345 350 Gln Gln Met Trp Ile Ser Lys Gln
Glu Tyr Asp Glu Ser Gly Pro Ser 355 360
365 Ile Val His Arg Lys Cys Phe 370
375 105140PRTHomo sapiens 105Met Ala Gly Trp Gln Ser Tyr Val Asp Asn Leu
Met Cys Asp Gly Cys 1 5 10
15 Cys Gln Glu Ala Ala Ile Val Gly Tyr Cys Asp Ala Lys Tyr Val Trp
20 25 30 Ala Ala
Thr Ala Gly Gly Val Phe Gln Ser Ile Thr Pro Ile Glu Ile 35
40 45 Asp Met Ile Val Gly Lys Asp
Arg Glu Gly Phe Phe Thr Asn Gly Leu 50 55
60 Thr Leu Gly Ala Lys Lys Cys Ser Val Ile Arg Asp
Ser Leu Tyr Val 65 70 75
80 Asp Gly Asp Cys Thr Met Asp Ile Arg Thr Lys Ser Gln Gly Gly Glu
85 90 95 Pro Thr Tyr
Asn Val Ala Val Gly Arg Ala Gly Arg Val Leu Val Phe 100
105 110 Val Met Gly Lys Glu Gly Val His
Gly Gly Gly Leu Asn Lys Lys Ala 115 120
125 Tyr Ser Met Ala Lys Tyr Leu Arg Asp Ser Gly Phe
130 135 140 106140PRTHomo sapiens 106Met
Ala Gly Trp Gln Ser Tyr Val Asp Asn Leu Met Cys Asp Gly Cys 1
5 10 15 Cys Gln Glu Ala Ala Ile
Val Gly Tyr Cys Asp Ala Lys Tyr Val Trp 20
25 30 Ala Ala Thr Ala Gly Gly Val Phe Gln Ser
Ile Thr Pro Ile Glu Ile 35 40
45 Asp Met Ile Val Gly Lys Asp Arg Glu Gly Phe Phe Thr Asn
Gly Leu 50 55 60
Thr Leu Gly Ala Lys Lys Cys Ser Val Ile Arg Asp Ser Leu Tyr Val 65
70 75 80 Asp Gly Asp Cys Thr
Met Asp Ile Arg Thr Lys Ser Gln Gly Gly Glu 85
90 95 Pro Thr Tyr Asn Val Ala Val Gly Arg Ala
Gly Arg Ala Leu Val Ile 100 105
110 Val Met Gly Lys Glu Gly Val His Gly Gly Thr Leu Asn Lys Lys
Ala 115 120 125 Tyr
Glu Leu Ala Leu Tyr Leu Arg Arg Ser Asp Val 130 135
140 107199PRTHomo sapiens 107Met Ala Asn Arg Gly Pro Ser
Tyr Gly Leu Ser Arg Glu Val Gln Glu 1 5
10 15 Lys Ile Glu Gln Lys Tyr Asp Ala Asp Leu Glu
Asn Lys Leu Val Asp 20 25
30 Trp Ile Ile Leu Gln Cys Ala Glu Asp Ile Glu His Pro Pro Pro
Gly 35 40 45 Arg
Ala His Phe Gln Lys Trp Leu Met Asp Gly Thr Val Leu Cys Lys 50
55 60 Leu Ile Asn Ser Leu Tyr
Pro Pro Gly Gln Glu Pro Ile Pro Lys Ile 65 70
75 80 Ser Glu Ser Lys Met Ala Phe Lys Gln Met Glu
Gln Ile Ser Gln Phe 85 90
95 Leu Lys Ala Ala Glu Thr Tyr Gly Val Arg Thr Thr Asp Ile Phe Gln
100 105 110 Thr Val
Asp Leu Trp Glu Gly Lys Asp Met Ala Ala Val Gln Arg Thr 115
120 125 Leu Met Ala Leu Gly Ser Val
Ala Val Thr Lys Asp Asp Gly Cys Tyr 130 135
140 Arg Gly Glu Pro Ser Trp Phe His Arg Lys Ala Gln
Gln Asn Arg Arg 145 150 155
160 Gly Phe Ser Glu Glu Gln Leu Arg Gln Gly Gln Asn Val Ile Gly Leu
165 170 175 Gln Met Gly
Ser Asn Lys Gly Ala Ser Gln Ala Gly Met Thr Gly Tyr 180
185 190 Gly Met Pro Arg Gln Ile Met
195 108673PRTHomo sapiens 108Met Ala Lys Pro Ala Gln
Gly Ala Lys Tyr Arg Gly Ser Ile His Asp 1 5
10 15 Phe Pro Gly Phe Asp Pro Asn Gln Asp Ala Glu
Ala Leu Tyr Thr Ala 20 25
30 Met Lys Gly Phe Gly Ser Asp Lys Glu Ala Ile Leu Asp Ile Ile
Thr 35 40 45 Ser
Arg Ser Asn Arg Gln Arg Gln Glu Val Cys Gln Ser Tyr Lys Ser 50
55 60 Leu Tyr Gly Lys Asp Leu
Ile Ala Asp Leu Lys Tyr Glu Leu Thr Gly 65 70
75 80 Lys Phe Glu Arg Leu Ile Val Gly Leu Met Arg
Pro Pro Ala Tyr Cys 85 90
95 Asp Ala Lys Glu Ile Lys Asp Ala Ile Ser Gly Ile Gly Thr Asp Glu
100 105 110 Lys Cys
Leu Ile Glu Ile Leu Ala Ser Arg Thr Asn Glu Gln Met His 115
120 125 Gln Leu Val Ala Ala Tyr Lys
Asp Ala Tyr Glu Arg Asp Leu Glu Ala 130 135
140 Asp Ile Ile Gly Asp Thr Ser Gly His Phe Gln Lys
Met Leu Val Val 145 150 155
160 Leu Leu Gln Gly Thr Arg Glu Glu Asp Asp Val Val Ser Glu Asp Leu
165 170 175 Val Gln Gln
Asp Val Gln Asp Leu Tyr Glu Ala Gly Glu Leu Lys Trp 180
185 190 Gly Thr Asp Glu Ala Gln Phe Ile
Tyr Ile Leu Gly Asn Arg Ser Lys 195 200
205 Gln His Leu Arg Leu Val Phe Asp Glu Tyr Leu Lys Thr
Thr Gly Lys 210 215 220
Pro Ile Glu Ala Ser Ile Arg Gly Glu Leu Ser Gly Asp Phe Glu Lys 225
230 235 240 Leu Met Leu Ala
Val Val Lys Cys Ile Arg Ser Thr Pro Glu Tyr Phe 245
250 255 Ala Glu Arg Leu Phe Lys Ala Met Lys
Gly Leu Gly Thr Arg Asp Asn 260 265
270 Thr Leu Ile Arg Ile Met Val Ser Arg Ser Glu Leu Asp Met
Leu Asp 275 280 285
Ile Arg Glu Ile Phe Arg Thr Lys Tyr Glu Lys Ser Leu Tyr Ser Met 290
295 300 Ile Lys Asn Asp Thr
Ser Gly Glu Tyr Lys Lys Thr Leu Leu Lys Leu 305 310
315 320 Ser Gly Gly Asp Asp Asp Ala Ala Gly Gln
Phe Phe Pro Glu Ala Ala 325 330
335 Gln Val Ala Tyr Gln Met Trp Glu Leu Ser Ala Val Ala Arg Val
Glu 340 345 350 Leu
Lys Gly Thr Val Arg Pro Ala Asn Asp Phe Asn Pro Asp Ala Asp 355
360 365 Ala Lys Ala Leu Arg Lys
Ala Met Lys Gly Leu Gly Thr Asp Glu Asp 370 375
380 Thr Ile Ile Asp Ile Ile Thr His Arg Ser Asn
Val Gln Arg Gln Gln 385 390 395
400 Ile Arg Gln Thr Phe Lys Ser His Phe Gly Arg Asp Leu Met Thr Asp
405 410 415 Leu Lys
Ser Glu Ile Ser Gly Asp Leu Ala Arg Leu Ile Leu Gly Leu 420
425 430 Met Met Pro Pro Ala His Tyr
Asp Ala Lys Gln Leu Lys Lys Ala Met 435 440
445 Glu Gly Ala Gly Thr Asp Glu Lys Ala Leu Ile Glu
Ile Leu Ala Thr 450 455 460
Arg Thr Asn Ala Glu Ile Arg Ala Ile Asn Glu Ala Tyr Lys Glu Asp 465
470 475 480 Tyr His Lys
Ser Leu Glu Asp Ala Leu Ser Ser Asp Thr Ser Gly His 485
490 495 Phe Arg Arg Ile Leu Ile Ser Leu
Ala Thr Gly His Arg Glu Glu Gly 500 505
510 Gly Glu Asn Leu Asp Gln Ala Arg Glu Asp Ala Gln Val
Ala Ala Glu 515 520 525
Ile Leu Glu Ile Ala Asp Thr Pro Ser Gly Asp Lys Thr Ser Leu Glu 530
535 540 Thr Arg Phe Met
Thr Ile Leu Cys Thr Arg Ser Tyr Pro His Leu Arg 545 550
555 560 Arg Val Phe Gln Glu Phe Ile Lys Met
Thr Asn Tyr Asp Val Glu His 565 570
575 Thr Ile Lys Lys Glu Met Ser Gly Asp Val Arg Asp Ala Phe
Val Ala 580 585 590
Ile Val Gln Ser Val Lys Asn Lys Pro Leu Phe Phe Ala Asp Lys Leu
595 600 605 Tyr Lys Ser Met
Lys Gly Ala Gly Thr Asp Glu Lys Thr Leu Thr Arg 610
615 620 Ile Met Val Ser Arg Ser Glu Ile
Asp Leu Leu Asn Ile Arg Arg Glu 625 630
635 640 Phe Ile Glu Lys Tyr Asp Lys Ser Leu His Gln Ala
Ile Glu Gly Asp 645 650
655 Thr Ser Gly Asp Phe Leu Lys Ala Leu Leu Ala Leu Cys Gly Gly Glu
660 665 670 Asp
109667PRTHomo sapiens 109Met Ala Lys Pro Ala Gln Gly Ala Lys Tyr Arg Gly
Ser Ile His Asp 1 5 10
15 Phe Pro Gly Phe Asp Pro Asn Gln Asp Ala Glu Ala Leu Tyr Thr Ala
20 25 30 Met Lys Gly
Phe Gly Ser Asp Lys Glu Ala Ile Leu Asp Ile Ile Thr 35
40 45 Ser Arg Ser Asn Arg Gln Arg Gln
Glu Val Cys Gln Ser Tyr Lys Ser 50 55
60 Leu Tyr Gly Lys Asp Leu Ile Ala Asp Leu Lys Tyr Glu
Leu Thr Gly 65 70 75
80 Lys Phe Glu Arg Leu Ile Val Gly Leu Met Arg Pro Pro Ala Tyr Cys
85 90 95 Asp Ala Lys Glu
Ile Lys Asp Ala Ile Ser Gly Ile Gly Thr Asp Glu 100
105 110 Lys Cys Leu Ile Glu Ile Leu Ala Ser
Arg Thr Asn Glu Gln Met His 115 120
125 Gln Leu Val Ala Ala Tyr Lys Asp Ala Tyr Glu Arg Asp Leu
Glu Ala 130 135 140
Asp Ile Ile Gly Asp Thr Ser Gly His Phe Gln Lys Met Leu Val Val 145
150 155 160 Leu Leu Gln Gly Thr
Arg Glu Glu Asp Asp Val Val Ser Glu Asp Leu 165
170 175 Val Gln Gln Asp Val Gln Asp Leu Tyr Glu
Ala Gly Glu Leu Lys Trp 180 185
190 Gly Thr Asp Glu Ala Gln Phe Ile Tyr Ile Leu Gly Asn Arg Ser
Lys 195 200 205 Gln
His Leu Arg Leu Val Phe Asp Glu Tyr Leu Lys Thr Thr Gly Lys 210
215 220 Pro Ile Glu Ala Ser Ile
Arg Gly Glu Leu Ser Gly Asp Phe Glu Lys 225 230
235 240 Leu Met Leu Ala Val Val Lys Cys Ile Arg Ser
Thr Pro Glu Tyr Phe 245 250
255 Ala Glu Arg Leu Phe Lys Ala Met Lys Gly Leu Gly Thr Arg Asp Asn
260 265 270 Thr Leu
Ile Arg Ile Met Val Ser Arg Ser Glu Leu Asp Met Leu Asp 275
280 285 Ile Arg Glu Ile Phe Arg Thr
Lys Tyr Glu Lys Ser Leu Tyr Ser Met 290 295
300 Ile Lys Asn Asp Thr Ser Gly Glu Tyr Lys Lys Thr
Leu Leu Lys Leu 305 310 315
320 Ser Gly Gly Asp Asp Asp Ala Ala Gly Gln Phe Phe Pro Glu Ala Ala
325 330 335 Gln Val Ala
Tyr Gln Met Trp Glu Leu Ser Ala Val Ala Arg Val Glu 340
345 350 Leu Lys Gly Thr Val Arg Pro Ala
Asn Asp Phe Asn Pro Asp Ala Asp 355 360
365 Ala Lys Ala Leu Arg Lys Ala Met Lys Gly Leu Gly Thr
Asp Glu Asp 370 375 380
Thr Ile Ile Asp Ile Ile Thr His Arg Ser Asn Val Gln Arg Gln Gln 385
390 395 400 Ile Arg Gln Thr
Phe Lys Ser His Phe Gly Arg Asp Leu Met Thr Asp 405
410 415 Leu Lys Ser Glu Ile Ser Gly Asp Leu
Ala Arg Leu Ile Leu Gly Leu 420 425
430 Met Met Pro Pro Ala His Tyr Asp Ala Lys Gln Leu Lys Lys
Ala Met 435 440 445
Glu Gly Ala Gly Thr Asp Glu Lys Ala Leu Ile Glu Ile Leu Ala Thr 450
455 460 Arg Thr Asn Ala Glu
Ile Arg Ala Ile Asn Glu Ala Tyr Lys Glu Asp 465 470
475 480 Tyr His Lys Ser Leu Glu Asp Ala Leu Ser
Ser Asp Thr Ser Gly His 485 490
495 Phe Arg Arg Ile Leu Ile Ser Leu Ala Thr Gly His Arg Glu Glu
Gly 500 505 510 Gly
Glu Asn Leu Asp Gln Ala Arg Glu Asp Ala Gln Glu Ile Ala Asp 515
520 525 Thr Pro Ser Gly Asp Lys
Thr Ser Leu Glu Thr Arg Phe Met Thr Ile 530 535
540 Leu Cys Thr Arg Ser Tyr Pro His Leu Arg Arg
Val Phe Gln Glu Phe 545 550 555
560 Ile Lys Met Thr Asn Tyr Asp Val Glu His Thr Ile Lys Lys Glu Met
565 570 575 Ser Gly
Asp Val Arg Asp Ala Phe Val Ala Ile Val Gln Ser Val Lys 580
585 590 Asn Lys Pro Leu Phe Phe Ala
Asp Lys Leu Tyr Lys Ser Met Lys Gly 595 600
605 Ala Gly Thr Asp Glu Lys Thr Leu Thr Arg Ile Met
Val Ser Arg Ser 610 615 620
Glu Ile Asp Leu Leu Asn Ile Arg Arg Glu Phe Ile Glu Lys Tyr Asp 625
630 635 640 Lys Ser Leu
His Gln Ala Ile Glu Gly Asp Thr Ser Gly Asp Phe Leu 645
650 655 Lys Ala Leu Leu Ala Leu Cys Gly
Gly Glu Asp 660 665 110499PRTHomo
sapiens 110Met Ser Phe Gly Ser Glu His Tyr Leu Cys Ser Ser Ser Ser Tyr
Arg 1 5 10 15 Lys
Val Phe Gly Asp Gly Ser Arg Leu Ser Ala Arg Leu Ser Gly Ala
20 25 30 Gly Gly Ala Gly Gly
Phe Arg Ser Gln Ser Leu Ser Arg Ser Asn Val 35
40 45 Ala Ser Ser Ala Ala Cys Ser Ser Ala
Ser Ser Leu Gly Leu Gly Leu 50 55
60 Ala Tyr Arg Arg Pro Pro Ala Ser Asp Gly Leu Asp Leu
Ser Gln Ala 65 70 75
80 Ala Ala Arg Thr Asn Glu Tyr Lys Ile Ile Arg Thr Asn Glu Lys Glu
85 90 95 Gln Leu Gln Gly
Leu Asn Asp Arg Phe Ala Val Phe Ile Glu Lys Val 100
105 110 His Gln Leu Glu Thr Gln Asn Arg Ala
Leu Glu Ala Glu Leu Ala Ala 115 120
125 Leu Arg Gln Arg His Ala Glu Pro Ser Arg Val Gly Glu Leu
Phe Gln 130 135 140
Arg Glu Leu Arg Asp Leu Arg Ala Gln Leu Glu Glu Ala Ser Ser Ala 145
150 155 160 Arg Ser Gln Ala Leu
Leu Glu Arg Asp Gly Leu Ala Glu Glu Val Gln 165
170 175 Arg Leu Arg Ala Arg Cys Glu Glu Glu Ser
Arg Gly Arg Glu Gly Ala 180 185
190 Glu Arg Ala Leu Lys Ala Gln Gln Arg Asp Val Asp Gly Ala Thr
Leu 195 200 205 Ala
Arg Leu Asp Leu Glu Lys Lys Val Glu Ser Leu Leu Asp Glu Leu 210
215 220 Ala Phe Val Arg Gln Val
His Asp Glu Glu Val Ala Glu Leu Leu Ala 225 230
235 240 Thr Leu Gln Ala Ser Ser Gln Ala Ala Ala Glu
Val Asp Val Thr Val 245 250
255 Ala Lys Pro Asp Leu Thr Ser Ala Leu Arg Glu Ile Arg Ala Gln Tyr
260 265 270 Glu Ser
Leu Ala Ala Lys Asn Leu Gln Ser Ala Glu Glu Trp Tyr Lys 275
280 285 Ser Lys Phe Ala Asn Leu Asn
Glu Gln Ala Ala Arg Ser Thr Glu Ala 290 295
300 Ile Arg Ala Ser Arg Glu Glu Ile His Glu Tyr Arg
Arg Gln Leu Gln 305 310 315
320 Ala Arg Thr Ile Glu Ile Glu Gly Leu Arg Gly Ala Asn Glu Ser Leu
325 330 335 Glu Arg Gln
Ile Leu Glu Leu Glu Glu Arg His Ser Ala Glu Val Ala 340
345 350 Gly Tyr Gln Asp Ser Ile Gly Gln
Leu Glu Asn Asp Leu Arg Asn Thr 355 360
365 Lys Ser Glu Met Ala Arg His Leu Arg Glu Tyr Gln Asp
Leu Leu Asn 370 375 380
Val Lys Met Ala Leu Asp Ile Glu Ile Ala Ala Tyr Arg Lys Leu Leu 385
390 395 400 Glu Gly Glu Glu
Thr Arg Phe Ser Thr Ser Gly Leu Ser Ile Ser Gly 405
410 415 Leu Asn Pro Leu Pro Asn Pro Ser Tyr
Leu Leu Pro Pro Arg Ile Leu 420 425
430 Ser Ala Thr Thr Ser Lys Val Ser Ser Thr Gly Leu Ser Leu
Lys Lys 435 440 445
Glu Glu Glu Glu Glu Glu Ala Ser Lys Val Ala Ser Lys Lys Thr Ser 450
455 460 Gln Ile Gly Glu Ser
Phe Glu Glu Ile Leu Glu Glu Thr Val Ile Ser 465 470
475 480 Thr Lys Lys Thr Glu Lys Ser Asn Ile Glu
Glu Thr Thr Ile Ser Ser 485 490
495 Gln Lys Ile 111543PRTHomo sapiens 111Met Ser Ser Phe Ser
Tyr Glu Pro Tyr Tyr Ser Thr Ser Tyr Lys Arg 1 5
10 15 Arg Tyr Val Glu Thr Pro Arg Val His Ile
Ser Ser Val Arg Ser Gly 20 25
30 Tyr Ser Thr Ala Arg Ser Ala Tyr Ser Ser Tyr Ser Ala Pro Val
Ser 35 40 45 Ser
Ser Leu Ser Val Arg Arg Ser Tyr Ser Ser Ser Ser Gly Ser Leu 50
55 60 Met Pro Ser Leu Glu Asn
Leu Asp Leu Ser Gln Val Ala Ala Ile Ser 65 70
75 80 Asn Asp Leu Lys Ser Ile Arg Thr Gln Glu Lys
Ala Gln Leu Gln Asp 85 90
95 Leu Asn Asp Arg Phe Ala Ser Phe Ile Glu Arg Val His Glu Leu Glu
100 105 110 Gln Gln
Asn Lys Val Leu Glu Ala Glu Leu Leu Val Leu Arg Gln Lys 115
120 125 His Ser Glu Pro Ser Arg Phe
Arg Ala Leu Tyr Glu Gln Glu Ile Arg 130 135
140 Asp Leu Arg Leu Ala Ala Glu Asp Ala Thr Asn Glu
Lys Gln Ala Leu 145 150 155
160 Gln Gly Glu Arg Glu Gly Leu Glu Glu Thr Leu Arg Asn Leu Gln Ala
165 170 175 Arg Tyr Glu
Glu Glu Val Leu Ser Arg Glu Asp Ala Glu Gly Arg Leu 180
185 190 Met Glu Ala Arg Lys Gly Ala Asp
Glu Ala Ala Leu Ala Arg Ala Glu 195 200
205 Leu Glu Lys Arg Ile Asp Ser Leu Met Asp Glu Ile Ser
Phe Leu Lys 210 215 220
Lys Val His Glu Glu Glu Ile Ala Glu Leu Gln Ala Gln Ile Gln Tyr 225
230 235 240 Ala Gln Ile Ser
Val Glu Met Asp Val Thr Lys Pro Asp Leu Ser Ala 245
250 255 Ala Leu Lys Asp Ile Arg Ala Gln Tyr
Glu Lys Leu Ala Ala Lys Asn 260 265
270 Met Gln Asn Ala Glu Glu Trp Phe Lys Ser Arg Phe Thr Val
Leu Thr 275 280 285
Glu Ser Ala Ala Lys Asn Thr Asp Ala Val Arg Ala Ala Lys Asp Glu 290
295 300 Val Ser Glu Ser Arg
Arg Leu Leu Lys Ala Lys Thr Leu Glu Ile Glu 305 310
315 320 Ala Cys Arg Gly Met Asn Glu Ala Leu Glu
Lys Gln Leu Gln Glu Leu 325 330
335 Glu Asp Lys Gln Asn Ala Asp Ile Ser Ala Met Gln Asp Thr Ile
Asn 340 345 350 Lys
Leu Glu Asn Glu Leu Arg Thr Thr Lys Ser Glu Met Ala Arg Tyr 355
360 365 Leu Lys Glu Tyr Gln Asp
Leu Leu Asn Val Lys Met Ala Leu Asp Ile 370 375
380 Glu Ile Ala Ala Tyr Arg Lys Leu Leu Glu Gly
Glu Glu Thr Arg Leu 385 390 395
400 Ser Phe Thr Ser Val Gly Ser Ile Thr Ser Gly Tyr Ser Gln Ser Ser
405 410 415 Gln Val
Phe Gly Arg Ser Ala Tyr Gly Gly Leu Gln Thr Ser Ser Tyr 420
425 430 Leu Met Ser Thr Arg Ser Phe
Pro Ser Tyr Tyr Thr Ser His Val Gln 435 440
445 Glu Glu Gln Ile Glu Val Glu Glu Thr Ile Glu Ala
Ala Lys Ala Glu 450 455 460
Glu Ala Lys Asp Glu Pro Pro Ser Glu Gly Glu Ala Glu Glu Glu Glu 465
470 475 480 Lys Asp Lys
Glu Glu Ala Glu Glu Glu Glu Ala Ala Glu Glu Glu Glu 485
490 495 Ala Ala Lys Glu Glu Ser Glu Glu
Ala Lys Glu Glu Glu Glu Gly Gly 500 505
510 Glu Gly Glu Glu Gly Glu Glu Thr Lys Glu Ala Glu Glu
Glu Glu Lys 515 520 525
Lys Val Glu Gly Ala Gly Glu Glu Gln Ala Ala Lys Lys Lys Asp 530
535 540 112432PRTHomo sapiens
112Met Glu Arg Arg Arg Ile Thr Ser Ala Ala Arg Arg Ser Tyr Val Ser 1
5 10 15 Ser Gly Glu Met
Met Val Gly Gly Leu Ala Pro Gly Arg Arg Leu Gly 20
25 30 Pro Gly Thr Arg Leu Ser Leu Ala Arg
Met Pro Pro Pro Leu Pro Thr 35 40
45 Arg Val Asp Phe Ser Leu Ala Gly Ala Leu Asn Ala Gly Phe
Lys Glu 50 55 60
Thr Arg Ala Ser Glu Arg Ala Glu Met Met Glu Leu Asn Asp Arg Phe 65
70 75 80 Ala Ser Tyr Ile Glu
Lys Val Arg Phe Leu Glu Gln Gln Asn Lys Ala 85
90 95 Leu Ala Ala Glu Leu Asn Gln Leu Arg Ala
Lys Glu Pro Thr Lys Leu 100 105
110 Ala Asp Val Tyr Gln Ala Glu Leu Arg Glu Leu Arg Leu Arg Leu
Asp 115 120 125 Gln
Leu Thr Ala Asn Ser Ala Arg Leu Glu Val Glu Arg Asp Asn Leu 130
135 140 Ala Gln Asp Leu Ala Thr
Val Arg Gln Lys Leu Gln Asp Glu Thr Asn 145 150
155 160 Leu Arg Leu Glu Ala Glu Asn Asn Leu Ala Ala
Tyr Arg Gln Glu Ala 165 170
175 Asp Glu Ala Thr Leu Ala Arg Leu Asp Leu Glu Arg Lys Ile Glu Ser
180 185 190 Leu Glu
Glu Glu Ile Arg Phe Leu Arg Lys Ile His Glu Glu Glu Val 195
200 205 Arg Glu Leu Gln Glu Gln Leu
Ala Arg Gln Gln Val His Val Glu Leu 210 215
220 Asp Val Ala Lys Pro Asp Leu Thr Ala Ala Leu Lys
Glu Ile Arg Thr 225 230 235
240 Gln Tyr Glu Ala Met Ala Ser Ser Asn Met His Glu Ala Glu Glu Trp
245 250 255 Tyr Arg Ser
Lys Phe Ala Asp Leu Thr Asp Ala Ala Ala Arg Asn Ala 260
265 270 Glu Leu Leu Arg Gln Ala Lys His
Glu Ala Asn Asp Tyr Arg Arg Gln 275 280
285 Leu Gln Ser Leu Thr Cys Asp Leu Glu Ser Leu Arg Gly
Thr Asn Glu 290 295 300
Ser Leu Glu Arg Gln Met Arg Glu Gln Glu Glu Arg His Val Arg Glu 305
310 315 320 Ala Ala Ser Tyr
Gln Glu Ala Leu Ala Arg Leu Glu Glu Glu Gly Gln 325
330 335 Ser Leu Lys Asp Glu Met Ala Arg His
Leu Gln Glu Tyr Gln Asp Leu 340 345
350 Leu Asn Val Lys Leu Ala Leu Asp Ile Glu Ile Ala Thr Tyr
Arg Lys 355 360 365
Leu Leu Glu Gly Glu Glu Asn Arg Ile Thr Ile Pro Val Gln Thr Phe 370
375 380 Ser Asn Leu Gln Ile
Arg Glu Thr Ser Leu Asp Thr Lys Ser Val Ser 385 390
395 400 Glu Gly His Leu Lys Arg Asn Ile Val Val
Lys Thr Val Glu Met Arg 405 410
415 Asp Gly Glu Val Ile Lys Glu Ser Lys Gln Glu His Lys Asp Val
Met 420 425 430
113431PRTHomo sapiens 113Met Glu Arg Arg Arg Ile Thr Ser Ala Ala Arg Arg
Ser Tyr Val Ser 1 5 10
15 Ser Gly Glu Met Met Val Gly Gly Leu Ala Pro Gly Arg Arg Leu Gly
20 25 30 Pro Gly Thr
Arg Leu Ser Leu Ala Arg Met Pro Pro Pro Leu Pro Thr 35
40 45 Arg Val Asp Phe Ser Leu Ala Gly
Ala Leu Asn Ala Gly Phe Lys Glu 50 55
60 Thr Arg Ala Ser Glu Arg Ala Glu Met Met Glu Leu Asn
Asp Arg Phe 65 70 75
80 Ala Ser Tyr Ile Glu Lys Val Arg Phe Leu Glu Gln Gln Asn Lys Ala
85 90 95 Leu Ala Ala Glu
Leu Asn Gln Leu Arg Ala Lys Glu Pro Thr Lys Leu 100
105 110 Ala Asp Val Tyr Gln Ala Glu Leu Arg
Glu Leu Arg Leu Arg Leu Asp 115 120
125 Gln Leu Thr Ala Asn Ser Ala Arg Leu Glu Val Glu Arg Asp
Asn Leu 130 135 140
Ala Gln Asp Leu Ala Thr Val Arg Gln Lys Leu Gln Asp Glu Thr Asn 145
150 155 160 Leu Arg Leu Glu Ala
Glu Asn Asn Leu Ala Ala Tyr Arg Gln Glu Ala 165
170 175 Asp Glu Ala Thr Leu Ala Arg Leu Asp Leu
Glu Arg Lys Ile Glu Ser 180 185
190 Leu Glu Glu Glu Ile Arg Phe Leu Arg Lys Ile His Glu Glu Glu
Val 195 200 205 Arg
Glu Leu Gln Glu Gln Leu Ala Arg Gln Gln Val His Val Glu Leu 210
215 220 Asp Val Ala Lys Pro Asp
Leu Thr Ala Ala Leu Lys Glu Ile Arg Thr 225 230
235 240 Gln Tyr Glu Ala Met Ala Ser Ser Asn Met His
Glu Ala Glu Glu Trp 245 250
255 Tyr Arg Ser Lys Phe Ala Asp Leu Thr Asp Ala Ala Ala Arg Asn Ala
260 265 270 Glu Leu
Leu Arg Gln Ala Lys His Glu Ala Asn Asp Tyr Arg Arg Gln 275
280 285 Leu Gln Ser Leu Thr Cys Asp
Leu Glu Ser Leu Arg Gly Thr Asn Glu 290 295
300 Ser Leu Glu Arg Gln Met Arg Glu Gln Glu Glu Arg
His Val Arg Glu 305 310 315
320 Ala Ala Ser Tyr Gln Glu Ala Leu Ala Arg Leu Glu Glu Glu Gly Gln
325 330 335 Ser Leu Lys
Asp Glu Met Ala Arg His Leu Gln Glu Tyr Gln Asp Leu 340
345 350 Leu Asn Val Lys Leu Ala Leu Asp
Ile Glu Ile Ala Thr Tyr Arg Lys 355 360
365 Leu Leu Glu Gly Glu Glu Asn Arg Ile Thr Ile Pro Val
Gln Thr Phe 370 375 380
Ser Asn Leu Gln Ile Arg Gly Gly Lys Ser Thr Lys Asp Gly Glu Asn 385
390 395 400 His Lys Val Thr
Arg Tyr Leu Lys Ser Leu Thr Ile Arg Val Ile Pro 405
410 415 Ile Gln Ala His Gln Ile Val Asn Gly
Thr Pro Pro Ala Arg Gly 420 425
430 114451PRTHomo sapiens 114Met Arg Glu Cys Ile Ser Ile His Val
Gly Gln Ala Gly Val Gln Ile 1 5 10
15 Gly Asn Ala Cys Trp Glu Leu Tyr Cys Leu Glu His Gly Ile
Gln Pro 20 25 30
Asp Gly Gln Met Pro Ser Asp Lys Thr Ile Gly Gly Gly Asp Asp Ser
35 40 45 Phe Asn Thr Phe
Phe Ser Glu Thr Gly Ala Gly Lys His Val Pro Arg 50
55 60 Ala Val Phe Val Asp Leu Glu Pro
Thr Val Ile Asp Glu Val Arg Thr 65 70
75 80 Gly Thr Tyr Arg Gln Leu Phe His Pro Glu Gln Leu
Ile Thr Gly Lys 85 90
95 Glu Asp Ala Ala Asn Asn Tyr Ala Arg Gly His Tyr Thr Ile Gly Lys
100 105 110 Glu Ile Ile
Asp Leu Val Leu Asp Arg Ile Arg Lys Leu Ala Asp Gln 115
120 125 Cys Thr Gly Leu Gln Gly Phe Leu
Val Phe His Ser Phe Gly Gly Gly 130 135
140 Thr Gly Ser Gly Phe Thr Ser Leu Leu Met Glu Arg Leu
Ser Val Asp 145 150 155
160 Tyr Gly Lys Lys Ser Lys Leu Glu Phe Ser Ile Tyr Pro Ala Pro Gln
165 170 175 Val Ser Thr Ala
Val Val Glu Pro Tyr Asn Ser Ile Leu Thr Thr His 180
185 190 Thr Thr Leu Glu His Ser Asp Cys Ala
Phe Met Val Asp Asn Glu Ala 195 200
205 Ile Tyr Asp Ile Cys Arg Arg Asn Leu Asp Ile Glu Arg Pro
Thr Tyr 210 215 220
Thr Asn Leu Asn Arg Leu Ile Ser Gln Ile Val Ser Ser Ile Thr Ala 225
230 235 240 Ser Leu Arg Phe Asp
Gly Ala Leu Asn Val Asp Leu Thr Glu Phe Gln 245
250 255 Thr Asn Leu Val Pro Tyr Pro Arg Ile His
Phe Pro Leu Ala Thr Tyr 260 265
270 Ala Pro Val Ile Ser Ala Glu Lys Ala Tyr His Glu Gln Leu Ser
Val 275 280 285 Ala
Glu Ile Thr Asn Ala Cys Phe Glu Pro Ala Asn Gln Met Val Lys 290
295 300 Cys Asp Pro Arg His Gly
Lys Tyr Met Ala Cys Cys Leu Leu Tyr Arg 305 310
315 320 Gly Asp Val Val Pro Lys Asp Val Asn Ala Ala
Ile Ala Thr Ile Lys 325 330
335 Thr Lys Arg Ser Ile Gln Phe Val Asp Trp Cys Pro Thr Gly Phe Lys
340 345 350 Val Gly
Ile Asn Tyr Gln Pro Pro Thr Val Val Pro Gly Gly Asp Leu 355
360 365 Ala Lys Val Gln Arg Ala Val
Cys Met Leu Ser Asn Thr Thr Ala Ile 370 375
380 Ala Glu Ala Trp Ala Arg Leu Asp His Lys Phe Asp
Leu Met Tyr Ala 385 390 395
400 Lys Arg Ala Phe Val His Trp Tyr Val Gly Glu Gly Met Glu Glu Gly
405 410 415 Glu Phe Ser
Glu Ala Arg Glu Asp Met Ala Ala Leu Glu Lys Asp Tyr 420
425 430 Glu Glu Val Gly Val Asp Ser Val
Glu Gly Glu Gly Glu Glu Glu Gly 435 440
445 Glu Glu Tyr 450 115445PRTHomo sapiens
115Met Arg Glu Ile Val His Ile Gln Ala Gly Gln Cys Gly Asn Gln Ile 1
5 10 15 Gly Ala Lys Phe
Trp Glu Val Ile Ser Asp Glu His Gly Ile Asp Pro 20
25 30 Thr Gly Ser Tyr His Gly Asp Ser Asp
Leu Gln Leu Glu Arg Ile Asn 35 40
45 Val Tyr Tyr Asn Glu Ala Thr Gly Asn Lys Tyr Val Pro Arg
Ala Ile 50 55 60
Leu Val Asp Leu Glu Pro Gly Thr Met Asp Ser Val Arg Ser Gly Pro 65
70 75 80 Phe Gly Gln Ile Phe
Arg Pro Asp Asn Phe Val Phe Gly Gln Ser Gly 85
90 95 Ala Gly Asn Asn Trp Ala Lys Gly His Tyr
Thr Glu Gly Ala Glu Leu 100 105
110 Val Asp Ser Val Leu Asp Val Val Arg Lys Glu Ser Glu Ser Cys
Asp 115 120 125 Cys
Leu Gln Gly Phe Gln Leu Thr His Ser Leu Gly Gly Gly Thr Gly 130
135 140 Ser Gly Met Gly Thr Leu
Leu Ile Ser Lys Ile Arg Glu Glu Tyr Pro 145 150
155 160 Asp Arg Ile Met Asn Thr Phe Ser Val Met Pro
Ser Pro Lys Val Ser 165 170
175 Asp Thr Val Val Glu Pro Tyr Asn Ala Thr Leu Ser Val His Gln Leu
180 185 190 Val Glu
Asn Thr Asp Glu Thr Tyr Cys Ile Asp Asn Glu Ala Leu Tyr 195
200 205 Asp Ile Cys Phe Arg Thr Leu
Lys Leu Thr Thr Pro Thr Tyr Gly Asp 210 215
220 Leu Asn His Leu Val Ser Ala Thr Met Ser Gly Val
Thr Thr Cys Leu 225 230 235
240 Arg Phe Pro Gly Gln Leu Asn Ala Asp Leu Arg Lys Leu Ala Val Asn
245 250 255 Met Val Pro
Phe Pro Arg Leu His Phe Phe Met Pro Gly Phe Ala Pro 260
265 270 Leu Thr Ser Arg Gly Ser Gln Gln
Tyr Arg Ala Leu Thr Val Pro Glu 275 280
285 Leu Thr Gln Gln Met Phe Asp Ser Lys Asn Met Met Ala
Ala Cys Asp 290 295 300
Pro Arg His Gly Arg Tyr Leu Thr Val Ala Ala Ile Phe Arg Gly Arg 305
310 315 320 Met Ser Met Lys
Glu Val Asp Glu Gln Met Leu Asn Val Gln Asn Lys 325
330 335 Asn Ser Ser Tyr Phe Val Glu Trp Ile
Pro Asn Asn Val Lys Thr Ala 340 345
350 Val Cys Asp Ile Pro Pro Arg Gly Leu Lys Met Ser Ala Thr
Phe Ile 355 360 365
Gly Asn Ser Thr Ala Ile Gln Glu Leu Phe Lys Arg Ile Ser Glu Gln 370
375 380 Phe Thr Ala Met Phe
Arg Arg Lys Ala Phe Leu His Trp Tyr Thr Gly 385 390
395 400 Glu Gly Met Asp Glu Met Glu Phe Thr Glu
Ala Glu Ser Asn Met Asn 405 410
415 Asp Leu Val Ser Glu Tyr Gln Gln Tyr Gln Asp Ala Thr Ala Asp
Glu 420 425 430 Gln
Gly Glu Phe Glu Glu Glu Glu Gly Glu Asp Glu Ala 435
440 445 116450PRTHomo sapiens 116Met Arg Glu Ile Val
His Ile Gln Ala Gly Gln Cys Gly Asn Gln Ile 1 5
10 15 Gly Ala Lys Phe Trp Glu Val Ile Ser Asp
Glu His Gly Ile Asp Pro 20 25
30 Ser Gly Asn Tyr Val Gly Asp Ser Asp Leu Gln Leu Glu Arg Ile
Ser 35 40 45 Val
Tyr Tyr Asn Glu Ala Ser Ser His Lys Tyr Val Pro Arg Ala Ile 50
55 60 Leu Val Asp Leu Glu Pro
Gly Thr Met Asp Ser Val Arg Ser Gly Ala 65 70
75 80 Phe Gly His Leu Phe Arg Pro Asp Asn Phe Ile
Phe Gly Gln Ser Gly 85 90
95 Ala Gly Asn Asn Trp Ala Lys Gly His Tyr Thr Glu Gly Ala Glu Leu
100 105 110 Val Asp
Ser Val Leu Asp Val Val Arg Lys Glu Cys Glu Asn Cys Asp 115
120 125 Cys Leu Gln Gly Phe Gln Leu
Thr His Ser Leu Gly Gly Gly Thr Gly 130 135
140 Ser Gly Met Gly Thr Leu Leu Ile Ser Lys Val Arg
Glu Glu Tyr Pro 145 150 155
160 Asp Arg Ile Met Asn Thr Phe Ser Val Val Pro Ser Pro Lys Val Ser
165 170 175 Asp Thr Val
Val Glu Pro Tyr Asn Ala Thr Leu Ser Ile His Gln Leu 180
185 190 Val Glu Asn Thr Asp Glu Thr Tyr
Cys Ile Asp Asn Glu Ala Leu Tyr 195 200
205 Asp Ile Cys Phe Arg Thr Leu Lys Leu Ala Thr Pro Thr
Tyr Gly Asp 210 215 220
Leu Asn His Leu Val Ser Ala Thr Met Ser Gly Val Thr Thr Ser Leu 225
230 235 240 Arg Phe Pro Gly
Gln Leu Asn Ala Asp Leu Arg Lys Leu Ala Val Asn 245
250 255 Met Val Pro Phe Pro Arg Leu His Phe
Phe Met Pro Gly Phe Ala Pro 260 265
270 Leu Thr Ala Arg Gly Ser Gln Gln Tyr Arg Ala Leu Thr Val
Pro Glu 275 280 285
Leu Thr Gln Gln Met Phe Asp Ala Lys Asn Met Met Ala Ala Cys Asp 290
295 300 Pro Arg His Gly Arg
Tyr Leu Thr Val Ala Thr Val Phe Arg Gly Arg 305 310
315 320 Met Ser Met Lys Glu Val Asp Glu Gln Met
Leu Ala Ile Gln Ser Lys 325 330
335 Asn Ser Ser Tyr Phe Val Glu Trp Ile Pro Asn Asn Val Lys Val
Ala 340 345 350 Val
Cys Asp Ile Pro Pro Arg Gly Leu Lys Met Ser Ser Thr Phe Ile 355
360 365 Gly Asn Ser Thr Ala Ile
Gln Glu Leu Phe Lys Arg Ile Ser Glu Gln 370 375
380 Phe Thr Ala Met Phe Arg Arg Lys Ala Phe Leu
His Trp Tyr Thr Gly 385 390 395
400 Glu Gly Met Asp Glu Met Glu Phe Thr Glu Ala Glu Ser Asn Met Asn
405 410 415 Asp Leu
Val Ser Glu Tyr Gln Gln Tyr Gln Asp Ala Thr Ala Glu Glu 420
425 430 Glu Gly Glu Met Tyr Glu Asp
Asp Glu Glu Glu Ser Glu Ala Gln Gly 435 440
445 Pro Lys 450 117572PRTHomo sapiens 117Met
Ser Tyr Gln Gly Lys Lys Asn Ile Pro Arg Ile Thr Ser Asp Arg 1
5 10 15 Leu Leu Ile Lys Gly Gly
Lys Ile Val Asn Asp Asp Gln Ser Phe Tyr 20
25 30 Ala Asp Ile Tyr Met Glu Asp Gly Leu Ile
Lys Gln Ile Gly Glu Asn 35 40
45 Leu Ile Val Pro Gly Gly Val Lys Thr Ile Glu Ala His Ser
Arg Met 50 55 60
Val Ile Pro Gly Gly Ile Asp Val His Thr Arg Phe Gln Met Pro Asp 65
70 75 80 Gln Gly Met Thr Ser
Ala Asp Asp Phe Phe Gln Gly Thr Lys Ala Ala 85
90 95 Leu Ala Gly Gly Thr Thr Met Ile Ile Asp
His Val Val Pro Glu Pro 100 105
110 Gly Thr Ser Leu Leu Ala Ala Phe Asp Gln Trp Arg Glu Trp Ala
Asp 115 120 125 Ser
Lys Ser Cys Cys Asp Tyr Ser Leu His Val Asp Ile Ser Glu Trp 130
135 140 His Lys Gly Ile Gln Glu
Glu Met Glu Ala Leu Val Lys Asp His Gly 145 150
155 160 Val Asn Ser Phe Leu Val Tyr Met Ala Phe Lys
Asp Arg Phe Gln Leu 165 170
175 Thr Asp Cys Gln Ile Tyr Glu Val Leu Ser Val Ile Arg Asp Ile Gly
180 185 190 Ala Ile
Ala Gln Val His Ala Glu Asn Gly Asp Ile Ile Ala Glu Glu 195
200 205 Gln Gln Arg Ile Leu Asp Leu
Gly Ile Thr Gly Pro Glu Gly His Val 210 215
220 Leu Ser Arg Pro Glu Glu Val Glu Ala Glu Ala Val
Asn Arg Ala Ile 225 230 235
240 Thr Ile Ala Asn Gln Thr Asn Cys Pro Leu Tyr Ile Thr Lys Val Met
245 250 255 Ser Lys Ser
Ser Ala Glu Val Ile Ala Gln Ala Arg Lys Lys Gly Thr 260
265 270 Val Val Tyr Gly Glu Pro Ile Thr
Ala Ser Leu Gly Thr Asp Gly Ser 275 280
285 His Tyr Trp Ser Lys Asn Trp Ala Lys Ala Ala Ala Phe
Val Thr Ser 290 295 300
Pro Pro Leu Ser Pro Asp Pro Thr Thr Pro Asp Phe Leu Asn Ser Leu 305
310 315 320 Leu Ser Cys Gly
Asp Leu Gln Val Thr Gly Ser Ala His Cys Thr Phe 325
330 335 Asn Thr Ala Gln Lys Ala Val Gly Lys
Asp Asn Phe Thr Leu Ile Pro 340 345
350 Glu Gly Thr Asn Gly Thr Glu Glu Arg Met Ser Val Ile Trp
Asp Lys 355 360 365
Ala Val Val Thr Gly Lys Met Asp Glu Asn Gln Phe Val Ala Val Thr 370
375 380 Ser Thr Asn Ala Ala
Lys Val Phe Asn Leu Tyr Pro Arg Lys Gly Arg 385 390
395 400 Ile Ala Val Gly Ser Asp Ala Asp Leu Val
Ile Trp Asp Pro Asp Ser 405 410
415 Val Lys Thr Ile Ser Ala Lys Thr His Asn Ser Ser Leu Glu Tyr
Asn 420 425 430 Ile
Phe Glu Gly Met Glu Cys Arg Gly Ser Pro Leu Val Val Ile Ser 435
440 445 Gln Gly Lys Ile Val Leu
Glu Asp Gly Thr Leu His Val Thr Glu Gly 450 455
460 Ser Gly Arg Tyr Ile Pro Arg Lys Pro Phe Pro
Asp Phe Val Tyr Lys 465 470 475
480 Arg Ile Lys Ala Arg Ser Arg Leu Ala Glu Leu Arg Gly Val Pro Arg
485 490 495 Gly Leu
Tyr Asp Gly Pro Val Cys Glu Val Ser Val Thr Pro Lys Thr 500
505 510 Val Thr Pro Ala Ser Ser Ala
Lys Thr Ser Pro Ala Lys Gln Gln Ala 515 520
525 Pro Pro Val Arg Asn Leu His Gln Ser Gly Phe Ser
Leu Ser Gly Ala 530 535 540
Gln Ile Asp Asp Asn Ile Pro Arg Arg Thr Thr Gln Arg Ile Val Ala 545
550 555 560 Pro Pro Gly
Gly Arg Ala Asn Ile Thr Ser Leu Gly 565
570 118572PRTHomo sapiens 118Met Ser Phe Gln Gly Lys Lys Ser Ile
Pro Arg Ile Thr Ser Asp Arg 1 5 10
15 Leu Leu Ile Arg Gly Gly Arg Ile Val Asn Asp Asp Gln Ser
Phe Tyr 20 25 30
Ala Asp Val His Val Glu Asp Gly Leu Ile Lys Gln Ile Gly Glu Asn
35 40 45 Leu Ile Val Pro
Gly Gly Ile Lys Thr Ile Asp Ala His Gly Leu Met 50
55 60 Val Leu Pro Gly Gly Val Asp Val
His Thr Arg Leu Gln Met Pro Val 65 70
75 80 Leu Gly Met Thr Pro Ala Asp Asp Phe Cys Gln Gly
Thr Lys Ala Ala 85 90
95 Leu Ala Gly Gly Thr Thr Met Ile Leu Asp His Val Phe Pro Asp Thr
100 105 110 Gly Val Ser
Leu Leu Ala Ala Tyr Glu Gln Trp Arg Glu Arg Ala Asp 115
120 125 Ser Ala Ala Cys Cys Asp Tyr Ser
Leu His Val Asp Ile Thr Arg Trp 130 135
140 His Glu Ser Ile Lys Glu Glu Leu Glu Ala Leu Val Lys
Glu Lys Gly 145 150 155
160 Val Asn Ser Phe Leu Val Phe Met Ala Tyr Lys Asp Arg Cys Gln Cys
165 170 175 Ser Asp Ser Gln
Met Tyr Glu Ile Phe Ser Ile Ile Arg Asp Leu Gly 180
185 190 Ala Leu Ala Gln Val His Ala Glu Asn
Gly Asp Ile Val Glu Glu Glu 195 200
205 Gln Lys Arg Leu Leu Glu Leu Gly Ile Thr Gly Pro Glu Gly
His Val 210 215 220
Leu Ser His Pro Glu Glu Val Glu Ala Glu Ala Val Tyr Arg Ala Val 225
230 235 240 Thr Ile Ala Lys Gln
Ala Asn Cys Pro Leu Tyr Val Thr Lys Val Met 245
250 255 Ser Lys Gly Ala Ala Asp Ala Ile Ala Gln
Ala Lys Arg Arg Gly Val 260 265
270 Val Val Phe Gly Glu Pro Ile Thr Ala Ser Leu Gly Thr Asp Gly
Ser 275 280 285 His
Tyr Trp Ser Lys Asn Trp Ala Lys Ala Ala Ala Phe Val Thr Ser 290
295 300 Pro Pro Val Asn Pro Asp
Pro Thr Thr Ala Asp His Leu Thr Cys Leu 305 310
315 320 Leu Ser Ser Gly Asp Leu Gln Val Thr Gly Ser
Ala His Cys Thr Phe 325 330
335 Thr Thr Ala Gln Lys Ala Val Gly Lys Asp Asn Phe Ala Leu Ile Pro
340 345 350 Glu Gly
Thr Asn Gly Ile Glu Glu Arg Met Ser Met Val Trp Glu Lys 355
360 365 Cys Val Ala Ser Gly Lys Met
Asp Glu Asn Glu Phe Val Ala Val Thr 370 375
380 Ser Thr Asn Ala Ala Lys Ile Phe Asn Phe Tyr Pro
Arg Lys Gly Arg 385 390 395
400 Val Ala Val Gly Ser Asp Ala Asp Leu Val Ile Trp Asn Pro Lys Ala
405 410 415 Thr Lys Ile
Ile Ser Ala Lys Thr His Asn Leu Asn Val Glu Tyr Asn 420
425 430 Ile Phe Glu Gly Val Glu Cys Arg
Gly Ala Pro Ala Val Val Ile Ser 435 440
445 Gln Gly Arg Val Ala Leu Glu Asp Gly Lys Met Phe Val
Thr Pro Gly 450 455 460
Ala Gly Arg Phe Val Pro Arg Lys Thr Phe Pro Asp Phe Val Tyr Lys 465
470 475 480 Arg Ile Lys Ala
Arg Asn Arg Leu Ala Glu Ile His Gly Val Pro Arg 485
490 495 Gly Leu Tyr Asp Gly Pro Val His Glu
Val Met Val Pro Ala Lys Pro 500 505
510 Gly Ser Gly Ala Pro Ala Arg Ala Ser Cys Pro Gly Lys Ile
Ser Val 515 520 525
Pro Pro Val Arg Asn Leu His Gln Ser Gly Phe Ser Leu Ser Gly Ser 530
535 540 Gln Ala Asp Asp His
Ile Ala Arg Arg Thr Ala Gln Lys Ile Met Ala 545 550
555 560 Pro Pro Gly Gly Arg Ser Asn Ile Thr Ser
Leu Ser 565 570 119227PRTHomo
sapiens 119Met Gly Gly Lys Leu Ser Lys Lys Lys Lys Gly Tyr Asn Val Asn
Asp 1 5 10 15 Glu
Lys Ala Lys Glu Lys Asp Lys Lys Ala Glu Gly Ala Ala Thr Glu
20 25 30 Glu Glu Gly Thr Pro
Lys Glu Ser Glu Pro Gln Ala Ala Ala Glu Pro 35
40 45 Ala Glu Ala Lys Glu Gly Lys Glu Lys
Pro Asp Gln Asp Ala Glu Gly 50 55
60 Lys Ala Glu Glu Lys Glu Gly Glu Lys Asp Ala Ala Ala
Ala Lys Glu 65 70 75
80 Glu Ala Pro Lys Ala Glu Pro Glu Lys Thr Glu Gly Ala Ala Glu Ala
85 90 95 Lys Ala Glu Pro
Pro Lys Ala Pro Glu Gln Glu Gln Ala Ala Pro Gly 100
105 110 Pro Ala Ala Gly Gly Glu Ala Pro Lys
Ala Ala Glu Ala Ala Ala Ala 115 120
125 Pro Ala Glu Ser Ala Ala Pro Ala Ala Gly Glu Glu Pro Ser
Lys Glu 130 135 140
Glu Gly Glu Pro Lys Lys Thr Glu Ala Pro Ala Ala Pro Ala Ala Gln 145
150 155 160 Glu Thr Lys Ser Asp
Gly Ala Pro Ala Ser Asp Ser Lys Pro Gly Ser 165
170 175 Ser Glu Ala Ala Pro Ser Ser Lys Glu Thr
Pro Ala Ala Thr Glu Ala 180 185
190 Pro Ser Ser Thr Pro Lys Ala Gln Gly Pro Ala Ala Ser Ala Glu
Glu 195 200 205 Pro
Lys Pro Val Glu Ala Pro Ala Ala Asn Ser Asp Gln Thr Val Thr 210
215 220 Val Lys Glu 225
120201PRTHomo sapiens 120Met Asn Pro Glu Tyr Asp Tyr Leu Phe Lys Leu Leu
Leu Ile Gly Asp 1 5 10
15 Ser Gly Val Gly Lys Ser Cys Leu Leu Leu Arg Phe Ala Asp Asp Thr
20 25 30 Tyr Thr Glu
Ser Tyr Ile Ser Thr Ile Gly Val Asp Phe Lys Ile Arg 35
40 45 Thr Ile Glu Leu Asp Gly Lys Thr
Ile Lys Leu Gln Ile Trp Asp Thr 50 55
60 Ala Gly Gln Glu Arg Phe Arg Thr Ile Thr Ser Ser Tyr
Tyr Arg Gly 65 70 75
80 Ala His Gly Ile Ile Val Val Tyr Asp Val Thr Asp Gln Glu Ser Tyr
85 90 95 Ala Asn Val Lys
Gln Trp Leu Gln Glu Ile Asp Arg Tyr Ala Ser Glu 100
105 110 Asn Val Asn Lys Leu Leu Val Gly Asn
Lys Ser Asp Leu Thr Thr Lys 115 120
125 Lys Val Val Asp Asn Thr Thr Ala Lys Glu Phe Ala Asp Ser
Leu Gly 130 135 140
Ile Pro Phe Leu Glu Thr Ser Ala Lys Asn Ala Thr Asn Val Glu Gln 145
150 155 160 Ala Phe Met Thr Met
Ala Ala Glu Ile Lys Lys Arg Met Gly Pro Gly 165
170 175 Ala Ala Ser Gly Gly Glu Arg Pro Asn Leu
Lys Ile Asp Ser Thr Pro 180 185
190 Val Lys Pro Ala Gly Gly Gly Cys Cys 195
200 121220PRTHomo sapiens 121Met Ala Ser Ala Thr Asp Ser Arg Tyr
Gly Gln Lys Glu Ser Ser Asp 1 5 10
15 Gln Asn Phe Asp Tyr Met Phe Lys Ile Leu Ile Ile Gly Asn
Ser Ser 20 25 30
Val Gly Lys Thr Ser Phe Leu Phe Arg Tyr Ala Asp Asp Ser Phe Thr
35 40 45 Pro Ala Phe Val
Ser Thr Val Gly Ile Asp Phe Lys Val Lys Thr Ile 50
55 60 Tyr Arg Asn Asp Lys Arg Ile Lys
Leu Gln Ile Trp Asp Thr Ala Gly 65 70
75 80 Gln Glu Arg Tyr Arg Thr Ile Thr Thr Ala Tyr Tyr
Arg Gly Ala Met 85 90
95 Gly Phe Ile Leu Met Tyr Asp Ile Thr Asn Glu Glu Ser Phe Asn Ala
100 105 110 Val Gln Asp
Trp Ser Thr Gln Ile Lys Thr Tyr Ser Trp Asp Asn Ala 115
120 125 Gln Val Leu Leu Val Gly Asn Lys
Cys Asp Met Glu Asp Glu Arg Val 130 135
140 Val Ser Ser Glu Arg Gly Arg Gln Leu Ala Asp His Leu
Gly Phe Glu 145 150 155
160 Phe Phe Glu Ala Ser Ala Lys Asp Asn Ile Asn Val Lys Gln Thr Phe
165 170 175 Glu Arg Leu Val
Asp Val Ile Cys Glu Lys Met Ser Glu Ser Leu Asp 180
185 190 Thr Ala Asp Pro Ala Val Thr Gly Ala
Lys Gln Gly Pro Gln Leu Ser 195 200
205 Asp Gln Gln Val Pro Pro His Gln Asp Cys Ala Cys 210
215 220 122208PRTHomo sapiens 122Met Ser
Thr Gly Gly Asp Phe Gly Asn Pro Leu Arg Lys Phe Lys Leu 1 5
10 15 Val Phe Leu Gly Glu Gln Ser
Val Gly Lys Thr Ser Leu Ile Thr Arg 20 25
30 Phe Met Tyr Asp Ser Phe Asp Asn Thr Tyr Gln Ala
Thr Ile Gly Ile 35 40 45
Asp Phe Leu Ser Lys Thr Met Tyr Leu Glu Asp Arg Thr Ile Arg Leu
50 55 60 Gln Leu Trp
Asp Thr Ala Gly Gln Glu Arg Phe Arg Ser Leu Ile Pro 65
70 75 80 Ser Tyr Ile Arg Asp Ser Ala
Ala Ala Val Val Val Tyr Asp Ile Thr 85
90 95 Asn Val Asn Ser Phe Gln Gln Thr Thr Lys Trp
Ile Asp Asp Val Arg 100 105
110 Thr Glu Arg Gly Ser Asp Val Ile Ile Met Leu Val Gly Asn Lys
Thr 115 120 125 Asp
Leu Ala Asp Lys Arg Gln Val Ser Ile Glu Glu Gly Glu Arg Lys 130
135 140 Ala Lys Glu Leu Asn Val
Met Phe Ile Glu Thr Ser Ala Lys Ala Gly 145 150
155 160 Tyr Asn Val Lys Gln Leu Phe Arg Arg Val Ala
Ala Ala Leu Pro Gly 165 170
175 Met Glu Ser Thr Gln Asp Arg Ser Arg Glu Asp Met Ile Asp Ile Lys
180 185 190 Leu Glu
Lys Pro Gln Glu Gln Pro Val Ser Glu Gly Gly Cys Ser Cys 195
200 205 123447PRTHomo sapiens
123Met Asp Glu Glu Tyr Asp Val Ile Val Leu Gly Thr Gly Leu Thr Glu 1
5 10 15 Cys Ile Leu Ser
Gly Ile Met Ser Val Asn Gly Lys Lys Val Leu His 20
25 30 Met Asp Arg Asn Pro Tyr Tyr Gly Gly
Glu Ser Ser Ser Ile Thr Pro 35 40
45 Leu Glu Glu Leu Tyr Lys Arg Phe Gln Leu Leu Glu Gly Pro
Pro Glu 50 55 60
Ser Met Gly Arg Gly Arg Asp Trp Asn Val Asp Leu Ile Pro Lys Phe 65
70 75 80 Leu Met Ala Asn Gly
Gln Leu Val Lys Met Leu Leu Tyr Thr Glu Val 85
90 95 Thr Arg Tyr Leu Asp Phe Lys Val Val Glu
Gly Ser Phe Val Tyr Lys 100 105
110 Gly Gly Lys Ile Tyr Lys Val Pro Ser Thr Glu Thr Glu Ala Leu
Ala 115 120 125 Ser
Asn Leu Met Gly Met Phe Glu Lys Arg Arg Phe Arg Lys Phe Leu 130
135 140 Val Phe Val Ala Asn Phe
Asp Glu Asn Asp Pro Lys Thr Phe Glu Gly 145 150
155 160 Val Asp Pro Gln Thr Thr Ser Met Arg Asp Val
Tyr Arg Lys Phe Asp 165 170
175 Leu Gly Gln Asp Val Ile Asp Phe Thr Gly His Ala Leu Ala Leu Tyr
180 185 190 Arg Thr
Asp Asp Tyr Leu Asp Gln Pro Cys Leu Glu Thr Val Asn Arg 195
200 205 Ile Lys Leu Tyr Ser Glu Ser
Leu Ala Arg Tyr Gly Lys Ser Pro Tyr 210 215
220 Leu Tyr Pro Leu Tyr Gly Leu Gly Glu Leu Pro Gln
Gly Phe Ala Arg 225 230 235
240 Leu Ser Ala Ile Tyr Gly Gly Thr Tyr Met Leu Asn Lys Pro Val Asp
245 250 255 Asp Ile Ile
Met Glu Asn Gly Lys Val Val Gly Val Lys Ser Glu Gly 260
265 270 Glu Val Ala Arg Cys Lys Gln Leu
Ile Cys Asp Pro Ser Tyr Ile Pro 275 280
285 Asp Arg Val Arg Lys Ala Gly Gln Val Ile Arg Ile Ile
Cys Ile Leu 290 295 300
Ser His Pro Ile Lys Asn Thr Asn Asp Ala Asn Ser Cys Gln Ile Ile 305
310 315 320 Ile Pro Gln Asn
Gln Val Asn Arg Lys Ser Asp Ile Tyr Val Cys Met 325
330 335 Ile Ser Tyr Ala His Asn Val Ala Ala
Gln Gly Lys Tyr Ile Ala Ile 340 345
350 Ala Ser Thr Thr Val Glu Thr Thr Asp Pro Glu Lys Glu Val
Glu Pro 355 360 365
Ala Leu Glu Leu Leu Glu Pro Ile Asp Gln Lys Phe Val Ala Ile Ser 370
375 380 Asp Leu Tyr Glu Pro
Ile Asp Asp Gly Cys Glu Ser Gln Val Phe Cys 385 390
395 400 Ser Cys Ser Tyr Asp Ala Thr Thr His Phe
Glu Thr Thr Cys Asn Asp 405 410
415 Ile Lys Asp Ile Tyr Lys Arg Met Ala Gly Thr Ala Phe Asp Phe
Glu 420 425 430 Asn
Met Lys Arg Lys Gln Asn Asp Val Phe Gly Glu Ala Glu Gln 435
440 445 124298PRTHomo sapiens 124Met
Asp Asn Ala Gly Lys Glu Arg Glu Ala Val Gln Leu Met Ala Glu 1
5 10 15 Ala Glu Lys Arg Val Lys
Ala Ser His Ser Phe Leu Arg Gly Leu Phe 20
25 30 Gly Gly Asn Thr Arg Ile Glu Glu Ala Cys
Glu Met Tyr Thr Arg Ala 35 40
45 Ala Asn Met Phe Lys Met Ala Lys Asn Trp Ser Ala Ala Gly
Asn Ala 50 55 60
Phe Cys Gln Ala Ala Lys Leu His Met Gln Leu Gln Ser Lys His Asp 65
70 75 80 Ser Ala Thr Ser Phe
Val Asp Ala Gly Asn Ala Tyr Lys Lys Ala Asp 85
90 95 Pro Gln Glu Ala Ile Asn Cys Leu Asn Ala
Ala Ile Asp Ile Tyr Thr 100 105
110 Asp Met Gly Arg Phe Thr Ile Ala Ala Lys His His Ile Thr Ile
Ala 115 120 125 Glu
Ile Tyr Glu Thr Glu Leu Val Asp Ile Glu Lys Ala Ile Ala His 130
135 140 Tyr Glu Gln Ser Ala Asp
Tyr Tyr Lys Gly Glu Glu Ser Asn Ser Ser 145 150
155 160 Ala Asn Lys Cys Leu Leu Lys Val Ala Ala Tyr
Ala Ala Gln Leu Glu 165 170
175 Gln Tyr Gln Lys Ala Ile Glu Ile Tyr Glu Gln Val Gly Ala Asn Thr
180 185 190 Met Asp
Asn Pro Leu Leu Lys Tyr Ser Ala Lys Asp Tyr Phe Phe Lys 195
200 205 Ala Ala Leu Cys His Phe Ile
Val Asp Glu Leu Asn Ala Lys Leu Ala 210 215
220 Leu Glu Lys Tyr Glu Glu Met Phe Pro Ala Phe Thr
Asp Ser Arg Glu 225 230 235
240 Cys Lys Leu Leu Lys Lys Leu Leu Glu Ala His Glu Glu Gln Asn Ser
245 250 255 Glu Ala Tyr
Thr Glu Ala Val Lys Glu Phe Asp Ser Ile Ser Arg Leu 260
265 270 Asp Gln Trp Leu Thr Thr Met Leu
Leu Arg Ile Lys Lys Ser Ile Gln 275 280
285 Gly Asp Gly Glu Gly Asp Gly Asp Leu Lys 290
295 125505PRTHomo sapiens 125Met Arg Leu Arg Arg
Leu Ala Leu Phe Pro Gly Val Ala Leu Leu Leu 1 5
10 15 Ala Ala Ala Arg Leu Ala Ala Ala Ser Asp
Val Leu Glu Leu Thr Asp 20 25
30 Asp Asn Phe Glu Ser Arg Ile Ser Asp Thr Gly Ser Ala Gly Leu
Met 35 40 45 Leu
Val Glu Phe Phe Ala Pro Trp Cys Gly His Cys Lys Arg Leu Ala 50
55 60 Pro Glu Tyr Glu Ala Ala
Ala Thr Arg Leu Lys Gly Ile Val Pro Leu 65 70
75 80 Ala Lys Val Asp Cys Thr Ala Asn Thr Asn Thr
Cys Asn Lys Tyr Gly 85 90
95 Val Ser Gly Tyr Pro Thr Leu Lys Ile Phe Arg Asp Gly Glu Glu Ala
100 105 110 Gly Ala
Tyr Asp Gly Pro Arg Thr Ala Asp Gly Ile Val Ser His Leu 115
120 125 Lys Lys Gln Ala Gly Pro Ala
Ser Val Pro Leu Arg Thr Glu Glu Glu 130 135
140 Phe Lys Lys Phe Ile Ser Asp Lys Asp Ala Ser Ile
Val Gly Phe Phe 145 150 155
160 Asp Asp Ser Phe Ser Glu Ala His Ser Glu Phe Leu Lys Ala Ala Ser
165 170 175 Asn Leu Arg
Asp Asn Tyr Arg Phe Ala His Thr Asn Val Glu Ser Leu 180
185 190 Val Asn Glu Tyr Asp Asp Asn Gly
Glu Gly Ile Ile Leu Phe Arg Pro 195 200
205 Ser His Leu Thr Asn Lys Phe Glu Asp Lys Thr Val Ala
Tyr Thr Glu 210 215 220
Gln Lys Met Thr Ser Gly Lys Ile Lys Lys Phe Ile Gln Glu Asn Ile 225
230 235 240 Phe Gly Ile Cys
Pro His Met Thr Glu Asp Asn Lys Asp Leu Ile Gln 245
250 255 Gly Lys Asp Leu Leu Ile Ala Tyr Tyr
Asp Val Asp Tyr Glu Lys Asn 260 265
270 Ala Lys Gly Ser Asn Tyr Trp Arg Asn Arg Val Met Met Val
Ala Lys 275 280 285
Lys Phe Leu Asp Ala Gly His Lys Leu Asn Phe Ala Val Ala Ser Arg 290
295 300 Lys Thr Phe Ser His
Glu Leu Ser Asp Phe Gly Leu Glu Ser Thr Ala 305 310
315 320 Gly Glu Ile Pro Val Val Ala Ile Arg Thr
Ala Lys Gly Glu Lys Phe 325 330
335 Val Met Gln Glu Glu Phe Ser Arg Asp Gly Lys Ala Leu Glu Arg
Phe 340 345 350 Leu
Gln Asp Tyr Phe Asp Gly Asn Leu Lys Arg Tyr Leu Lys Ser Glu 355
360 365 Pro Ile Pro Glu Ser Asn
Asp Gly Pro Val Lys Val Val Val Ala Glu 370 375
380 Asn Phe Asp Glu Ile Val Asn Asn Glu Asn Lys
Asp Val Leu Ile Glu 385 390 395
400 Phe Tyr Ala Pro Trp Cys Gly His Cys Lys Asn Leu Glu Pro Lys Tyr
405 410 415 Lys Glu
Leu Gly Glu Lys Leu Ser Lys Asp Pro Asn Ile Val Ile Ala 420
425 430 Lys Met Asp Ala Thr Ala Asn
Asp Val Pro Ser Pro Tyr Glu Val Arg 435 440
445 Gly Phe Pro Thr Ile Tyr Phe Ser Pro Ala Asn Lys
Lys Leu Asn Pro 450 455 460
Lys Lys Tyr Glu Gly Gly Arg Glu Leu Ser Asp Phe Ile Ser Tyr Leu 465
470 475 480 Gln Arg Glu
Ala Thr Asn Pro Pro Val Ile Gln Glu Glu Lys Pro Lys 485
490 495 Lys Lys Lys Lys Ala Gln Glu Asp
Leu 500 505 126170PRTMus musculus 126Met Gly
Asn Glu Ala Ser Tyr Pro Leu Glu Met Cys Ser His Phe Asp 1 5
10 15 Ala Asp Glu Ile Lys Arg Leu
Gly Lys Arg Phe Lys Lys Leu Asp Leu 20 25
30 Asp Asn Ser Gly Ser Leu Ser Val Glu Glu Phe Met
Ser Leu Pro Glu 35 40 45
Leu Gln Gln Asn Pro Leu Val Gln Arg Val Ile Asp Ile Phe Asp Thr
50 55 60 Asp Gly Asn
Gly Glu Val Asp Phe Lys Glu Phe Ile Glu Gly Val Ser 65
70 75 80 Gln Phe Ser Val Lys Gly Asp
Lys Glu Gln Lys Leu Arg Phe Ala Phe 85
90 95 Arg Ile Tyr Asp Met Asp Lys Asp Gly Tyr Ile
Ser Asn Gly Glu Leu 100 105
110 Phe Gln Val Leu Lys Met Met Val Gly Asn Asn Leu Lys Asp Thr
Gln 115 120 125 Leu
Gln Gln Ile Val Asp Lys Thr Ile Ile Asn Ala Asp Lys Asp Gly 130
135 140 Asp Gly Arg Ile Ser Phe
Glu Glu Phe Cys Ala Val Val Gly Gly Leu 145 150
155 160 Asp Ile His Lys Lys Met Val Val Asp Val
165 170 127170PRTHomo sapiens 127 Met Gly Asn
Glu Ala Ser Tyr Pro Leu Glu Met Cys Ser His Phe Asp 1 5
10 15 Ala Asp Glu Ile Lys Arg Leu Gly
Lys Arg Phe Lys Lys Leu Asp Leu 20 25
30 Asp Asn Ser Gly Ser Leu Ser Val Glu Glu Phe Met Ser
Leu Pro Glu 35 40 45
Leu Gln Gln Asn Pro Leu Val Gln Arg Val Ile Asp Ile Phe Asp Thr 50
55 60 Asp Gly Asn Gly
Glu Val Asp Phe Lys Glu Phe Ile Glu Gly Val Ser 65 70
75 80 Gln Phe Ser Val Lys Gly Asp Lys Glu
Gln Lys Leu Arg Phe Ala Phe 85 90
95 Arg Ile Tyr Asp Met Asp Lys Asp Gly Tyr Ile Ser Asn Gly
Glu Leu 100 105 110
Phe Gln Val Leu Lys Met Met Val Gly Asn Asn Leu Lys Asp Thr Gln
115 120 125 Leu Gln Gln Ile
Val Asp Lys Thr Ile Ile Asn Ala Asp Lys Asp Gly 130
135 140 Asp Gly Arg Ile Ser Phe Glu Glu
Phe Cys Ala Val Val Gly Gly Leu 145 150
155 160 Asp Ile His Lys Lys Met Val Val Asp Val
165 170 128261PRTHomo sapiens 128 Met Ala Glu Ser
His Leu Gln Ser Ser Leu Ile Thr Ala Ser Gln Phe 1 5
10 15 Phe Glu Ile Trp Leu His Phe Asp Ala
Asp Gly Ser Gly Tyr Leu Glu 20 25
30 Gly Lys Glu Leu Gln Asn Leu Ile Gln Glu Leu Gln Gln Ala
Arg Lys 35 40 45
Lys Ala Gly Leu Glu Leu Ser Pro Glu Met Lys Thr Phe Val Asp Gln 50
55 60 Tyr Gly Gln Arg Asp
Asp Gly Lys Ile Gly Ile Val Glu Leu Ala His 65 70
75 80 Val Leu Pro Thr Glu Glu Asn Phe Leu Leu
Leu Phe Arg Cys Gln Gln 85 90
95 Leu Lys Ser Cys Glu Glu Phe Met Lys Thr Trp Arg Lys Tyr Asp
Thr 100 105 110 Asp
His Ser Gly Phe Ile Glu Thr Glu Glu Leu Lys Asn Phe Leu Lys 115
120 125 Asp Leu Leu Glu Lys Ala
Asn Lys Thr Val Asp Asp Thr Lys Leu Ala 130 135
140 Glu Tyr Thr Asp Leu Met Leu Lys Leu Phe Asp
Ser Asn Asn Asp Gly 145 150 155
160 Lys Leu Glu Leu Thr Glu Met Ala Arg Leu Leu Pro Val Gln Glu Asn
165 170 175 Phe Leu
Leu Lys Phe Gln Gly Ile Lys Met Cys Gly Lys Glu Phe Asn 180
185 190 Lys Ala Phe Glu Leu Tyr Asp
Gln Asp Gly Asn Gly Tyr Ile Asp Glu 195 200
205 Asn Glu Leu Asp Ala Leu Leu Lys Asp Leu Cys Glu
Lys Asn Lys Gln 210 215 220
Asp Leu Asp Ile Asn Asn Ile Thr Thr Tyr Lys Lys Asn Ile Met Ala 225
230 235 240 Leu Ser Asp
Gly Gly Lys Leu Tyr Arg Thr Asp Leu Ala Leu Ile Leu 245
250 255 Cys Ala Gly Asp Asn
260 129271PRTHomo sapiens 129Met Ala Gly Pro Gln Gln Gln Pro Pro Tyr
Leu His Leu Ala Glu Leu 1 5 10
15 Thr Ala Ser Gln Phe Leu Glu Ile Trp Lys His Phe Asp Ala Asp
Gly 20 25 30 Asn
Gly Tyr Ile Glu Gly Lys Glu Leu Glu Asn Phe Phe Gln Glu Leu 35
40 45 Glu Lys Ala Arg Lys Gly
Ser Gly Met Met Ser Lys Ser Asp Asn Phe 50 55
60 Gly Glu Lys Met Lys Glu Phe Met Gln Lys Tyr
Asp Lys Asn Ser Asp 65 70 75
80 Gly Lys Ile Glu Met Ala Glu Leu Ala Gln Ile Leu Pro Thr Glu Glu
85 90 95 Asn Phe
Leu Leu Cys Phe Arg Gln His Val Gly Ser Ser Ala Glu Phe 100
105 110 Met Glu Ala Trp Arg Lys Tyr
Asp Thr Asp Arg Ser Gly Tyr Ile Glu 115 120
125 Ala Asn Glu Leu Lys Gly Phe Leu Ser Asp Leu Leu
Lys Lys Ala Asn 130 135 140
Arg Pro Tyr Asp Glu Pro Lys Leu Gln Glu Tyr Thr Gln Thr Ile Leu 145
150 155 160 Arg Met Phe
Asp Leu Asn Gly Asp Gly Lys Leu Gly Leu Ser Glu Met 165
170 175 Ser Arg Leu Leu Pro Val Gln Glu
Asn Phe Leu Leu Lys Phe Gln Gly 180 185
190 Met Lys Leu Thr Ser Glu Glu Phe Asn Ala Ile Phe Thr
Phe Tyr Asp 195 200 205
Lys Asp Arg Ser Gly Tyr Ile Asp Glu His Glu Leu Asp Ala Leu Leu 210
215 220 Lys Asp Leu Tyr
Glu Lys Asn Lys Lys Glu Met Asn Ile Gln Gln Leu 225 230
235 240 Thr Asn Tyr Arg Lys Ser Val Met Ser
Leu Ala Glu Ala Gly Lys Leu 245 250
255 Tyr Arg Lys Asp Leu Glu Ile Val Leu Cys Ser Glu Pro Pro
Met 260 265 270
130191PRTHomo sapiens 130Met Gly Lys Gln Asn Ser Lys Leu Ala Pro Glu Val
Met Glu Asp Leu 1 5 10
15 Val Lys Ser Thr Glu Phe Asn Glu His Glu Leu Lys Gln Trp Tyr Lys
20 25 30 Gly Phe Leu
Lys Asp Cys Pro Ser Gly Arg Leu Asn Leu Glu Glu Phe 35
40 45 Gln Gln Leu Tyr Val Lys Phe Phe
Pro Tyr Gly Asp Ala Ser Lys Phe 50 55
60 Ala Gln His Ala Phe Arg Thr Phe Asp Lys Asn Gly Asp
Gly Thr Ile 65 70 75
80 Asp Phe Arg Glu Phe Ile Cys Ala Leu Ser Ile Thr Ser Arg Gly Ser
85 90 95 Phe Glu Gln Lys
Leu Asn Trp Ala Phe Asn Met Tyr Asp Leu Asp Gly 100
105 110 Asp Gly Lys Ile Thr Arg Val Glu Met
Leu Glu Ile Ile Glu Ala Ile 115 120
125 Tyr Lys Met Val Gly Thr Val Ile Met Met Lys Met Asn Glu
Asp Gly 130 135 140
Leu Thr Pro Glu Gln Arg Val Asp Lys Ile Phe Ser Lys Met Asp Lys 145
150 155 160 Asn Lys Asp Asp Gln
Ile Thr Leu Asp Glu Phe Lys Glu Ala Ala Lys 165
170 175 Ser Asp Pro Ser Ile Val Leu Leu Leu Gln
Cys Asp Ile Gln Lys 180 185
190 131253PRTHomo sapiens 131Met Ala Leu Ser Met Pro Leu Asn Gly Leu
Lys Glu Glu Asp Lys Glu 1 5 10
15 Pro Leu Ile Glu Leu Phe Val Lys Ala Gly Ser Asp Gly Glu Ser
Ile 20 25 30 Gly
Asn Cys Pro Phe Ser Gln Arg Leu Phe Met Ile Leu Trp Leu Lys 35
40 45 Gly Val Val Phe Ser Val
Thr Thr Val Asp Leu Lys Arg Lys Pro Ala 50 55
60 Asp Leu Gln Asn Leu Ala Pro Gly Thr His Pro
Pro Phe Ile Thr Phe 65 70 75
80 Asn Ser Glu Val Lys Thr Asp Val Asn Lys Ile Glu Glu Phe Leu Glu
85 90 95 Glu Val
Leu Cys Pro Pro Lys Tyr Leu Lys Leu Ser Pro Lys His Pro 100
105 110 Glu Ser Asn Thr Ala Gly Met
Asp Ile Phe Ala Lys Phe Ser Ala Tyr 115 120
125 Ile Lys Asn Ser Arg Pro Glu Ala Asn Glu Ala Leu
Glu Arg Gly Leu 130 135 140
Leu Lys Thr Leu Gln Lys Leu Asp Glu Tyr Leu Asn Ser Pro Leu Pro 145
150 155 160 Asp Glu Ile
Asp Glu Asn Ser Met Glu Asp Ile Lys Phe Ser Thr Arg 165
170 175 Lys Phe Leu Asp Gly Asn Glu Met
Thr Leu Ala Asp Cys Asn Leu Leu 180 185
190 Pro Lys Leu His Ile Val Lys Val Val Ala Lys Lys Tyr
Arg Asn Phe 195 200 205
Asp Ile Pro Lys Glu Met Thr Gly Ile Trp Arg Tyr Leu Thr Asn Ala 210
215 220 Tyr Ser Arg Asp
Glu Phe Thr Asn Thr Cys Pro Ser Asp Lys Glu Val 225 230
235 240 Glu Ile Ala Tyr Ser Asp Val Ala Lys
Arg Leu Thr Lys 245 250
132187PRTHomo sapiens 132 Met Pro Val Asp Leu Ser Lys Trp Ser Gly Pro Leu
Ser Leu Gln Glu 1 5 10
15 Val Asp Glu Gln Pro Gln His Pro Leu His Val Thr Tyr Ala Gly Ala
20 25 30 Ala Val Asp
Glu Leu Gly Lys Val Leu Thr Pro Thr Gln Val Lys Asn 35
40 45 Arg Pro Thr Ser Ile Ser Trp Asp
Gly Leu Asp Ser Gly Lys Leu Tyr 50 55
60 Thr Leu Val Leu Thr Asp Pro Asp Ala Pro Ser Arg Lys
Asp Pro Lys 65 70 75
80 Tyr Arg Glu Trp His His Phe Leu Val Val Asn Met Lys Gly Asn Asp
85 90 95 Ile Ser Ser Gly
Thr Val Leu Ser Asp Tyr Val Gly Ser Gly Pro Pro 100
105 110 Lys Gly Thr Gly Leu His Arg Tyr Val
Trp Leu Val Tyr Glu Gln Asp 115 120
125 Arg Pro Leu Lys Cys Asp Glu Pro Ile Leu Ser Asn Arg Ser
Gly Asp 130 135 140
His Arg Gly Lys Phe Lys Val Ala Ser Phe Arg Lys Lys Tyr Glu Leu 145
150 155 160 Arg Ala Pro Val Ala
Gly Thr Cys Tyr Gln Ala Glu Trp Asp Asp Tyr 165
170 175 Val Pro Lys Leu Tyr Glu Gln Leu Ser Gly
Lys 180 185 133245PRTHomo sapiens
133Met Asp Lys Asn Glu Leu Val Gln Lys Ala Lys Leu Ala Glu Gln Ala 1
5 10 15 Glu Arg Tyr Asp
Asp Met Ala Ala Cys Met Lys Ser Val Thr Glu Gln 20
25 30 Gly Ala Glu Leu Ser Asn Glu Glu Arg
Asn Leu Leu Ser Val Ala Tyr 35 40
45 Lys Asn Val Val Gly Ala Arg Arg Ser Ser Trp Arg Val Val
Ser Ser 50 55 60
Ile Glu Gln Lys Thr Glu Gly Ala Glu Lys Lys Gln Gln Met Ala Arg 65
70 75 80 Glu Tyr Arg Glu Lys
Ile Glu Thr Glu Leu Arg Asp Ile Cys Asn Asp 85
90 95 Val Leu Ser Leu Leu Glu Lys Phe Leu Ile
Pro Asn Ala Ser Gln Ala 100 105
110 Glu Ser Lys Val Phe Tyr Leu Lys Met Lys Gly Asp Tyr Tyr Arg
Tyr 115 120 125 Leu
Ala Glu Val Ala Ala Gly Asp Asp Lys Lys Gly Ile Val Asp Gln 130
135 140 Ser Gln Gln Ala Tyr Gln
Glu Ala Phe Glu Ile Ser Lys Lys Glu Met 145 150
155 160 Gln Pro Thr His Pro Ile Arg Leu Gly Leu Ala
Leu Asn Phe Ser Val 165 170
175 Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Glu Lys Ala Cys Ser Leu Ala
180 185 190 Lys Thr
Ala Phe Asp Glu Ala Ile Ala Glu Leu Asp Thr Leu Ser Glu 195
200 205 Glu Ser Tyr Lys Asp Ser Thr
Leu Ile Met Gln Leu Leu Arg Asp Asn 210 215
220 Leu Thr Leu Trp Thr Ser Asp Thr Gln Gly Asp Glu
Ala Glu Ala Gly 225 230 235
240 Glu Gly Gly Glu Asn 245 134255PRTHomo sapiens
134Met Asp Asp Arg Glu Asp Leu Val Tyr Gln Ala Lys Leu Ala Glu Gln 1
5 10 15 Ala Glu Arg Tyr
Asp Glu Met Val Glu Ser Met Lys Lys Val Ala Gly 20
25 30 Met Asp Val Glu Leu Thr Val Glu Glu
Arg Asn Leu Leu Ser Val Ala 35 40
45 Tyr Lys Asn Val Ile Gly Ala Arg Arg Ala Ser Trp Arg Ile
Ile Ser 50 55 60
Ser Ile Glu Gln Lys Glu Glu Asn Lys Gly Gly Glu Asp Lys Leu Lys 65
70 75 80 Met Ile Arg Glu Tyr
Arg Gln Met Val Glu Thr Glu Leu Lys Leu Ile 85
90 95 Cys Cys Asp Ile Leu Asp Val Leu Asp Lys
His Leu Ile Pro Ala Ala 100 105
110 Asn Thr Gly Glu Ser Lys Val Phe Tyr Tyr Lys Met Lys Gly Asp
Tyr 115 120 125 His
Arg Tyr Leu Ala Glu Phe Ala Thr Gly Asn Asp Arg Lys Glu Ala 130
135 140 Ala Glu Asn Ser Leu Val
Ala Tyr Lys Ala Ala Ser Asp Ile Ala Met 145 150
155 160 Thr Glu Leu Pro Pro Thr His Pro Ile Arg Leu
Gly Leu Ala Leu Asn 165 170
175 Phe Ser Val Phe Tyr Tyr Glu Ile Leu Asn Ser Pro Asp Arg Ala Cys
180 185 190 Arg Leu
Ala Lys Ala Ala Phe Asp Asp Ala Ile Ala Glu Leu Asp Thr 195
200 205 Leu Ser Glu Glu Ser Tyr Lys
Asp Ser Thr Leu Ile Met Gln Leu Leu 210 215
220 Arg Asp Asn Leu Thr Leu Trp Thr Ser Asp Met Gln
Gly Asp Gly Glu 225 230 235
240 Glu Gln Asn Lys Glu Ala Leu Gln Asp Val Glu Asp Glu Asn Gln
245 250 255 135199PRTHomo sapiens
135 Met Ser Ser Gly Asn Ala Lys Ile Gly His Pro Ala Pro Asn Phe Lys 1
5 10 15 Ala Thr Ala Val
Met Pro Asp Gly Gln Phe Lys Asp Ile Ser Leu Ser 20
25 30 Asp Tyr Lys Gly Lys Tyr Val Val Phe
Phe Phe Tyr Pro Leu Asp Phe 35 40
45 Thr Phe Val Cys Pro Thr Glu Ile Ile Ala Phe Ser Asp Arg
Ala Glu 50 55 60
Glu Phe Lys Lys Leu Asn Cys Gln Val Ile Gly Ala Ser Val Asp Ser 65
70 75 80 His Phe Cys His Leu
Ala Trp Val Asn Thr Pro Lys Lys Gln Gly Gly 85
90 95 Leu Gly Pro Met Asn Ile Pro Leu Val Ser
Asp Pro Lys Arg Thr Ile 100 105
110 Ala Gln Asp Tyr Gly Val Leu Lys Ala Asp Glu Gly Ile Ser Phe
Arg 115 120 125 Gly
Leu Phe Ile Ile Asp Asp Lys Gly Ile Leu Arg Gln Ile Thr Val 130
135 140 Asn Asp Leu Pro Val Gly
Arg Ser Val Asp Glu Thr Leu Arg Leu Val 145 150
155 160 Gln Ala Phe Gln Phe Thr Asp Lys His Gly Glu
Val Cys Pro Ala Gly 165 170
175 Trp Lys Pro Gly Ser Asp Thr Ile Lys Pro Asp Val Gln Lys Ser Lys
180 185 190 Glu Tyr
Phe Ser Lys Gln Lys 195 136256PRTHomo sapiens
136Met Ala Ala Ala Val Gly Arg Leu Leu Arg Ala Ser Val Ala Arg His 1
5 10 15 Val Ser Ala Ile
Pro Trp Gly Ile Ser Ala Thr Ala Ala Leu Arg Pro 20
25 30 Ala Ala Cys Gly Arg Thr Ser Leu Thr
Asn Leu Leu Cys Ser Gly Ser 35 40
45 Ser Gln Ala Lys Leu Phe Ser Thr Ser Ser Ser Cys His Ala
Pro Ala 50 55 60
Val Thr Gln His Ala Pro Tyr Phe Lys Gly Thr Ala Val Val Asn Gly 65
70 75 80 Glu Phe Lys Asp Leu
Ser Leu Asp Asp Phe Lys Gly Lys Tyr Leu Val 85
90 95 Leu Phe Phe Tyr Pro Leu Asp Phe Thr Phe
Val Cys Pro Thr Glu Ile 100 105
110 Val Ala Phe Ser Asp Lys Ala Asn Glu Phe His Asp Val Asn Cys
Glu 115 120 125 Val
Val Ala Val Ser Val Asp Ser His Phe Ser His Leu Ala Trp Ile 130
135 140 Asn Thr Pro Arg Lys Asn
Gly Gly Leu Gly His Met Asn Ile Ala Leu 145 150
155 160 Leu Ser Asp Leu Thr Lys Gln Ile Ser Arg Asp
Tyr Gly Val Leu Leu 165 170
175 Glu Gly Ser Gly Leu Ala Leu Arg Gly Leu Phe Ile Ile Asp Pro Asn
180 185 190 Gly Val
Ile Lys His Leu Ser Val Asn Asp Leu Pro Val Gly Arg Ser 195
200 205 Val Glu Glu Thr Leu Arg Leu
Val Lys Ala Phe Gln Tyr Val Glu Thr 210 215
220 His Gly Glu Val Cys Pro Ala Asn Trp Thr Pro Asp
Ser Pro Thr Ile 225 230 235
240 Lys Pro Ser Pro Ala Ala Ser Lys Glu Tyr Phe Gln Lys Val Asn Gln
245 250 255 137312PRTHomo
sapiens 137 Met Glu Glu Glu Cys Arg Val Leu Ser Ile Gln Ser His Val Ile
Arg 1 5 10 15 Gly
Tyr Val Gly Asn Arg Ala Ala Thr Phe Pro Leu Gln Val Leu Gly
20 25 30 Phe Glu Ile Asp Ala
Val Asn Ser Val Gln Phe Ser Asn His Thr Gly 35
40 45 Tyr Ala His Trp Lys Gly Gln Val Leu
Asn Ser Asp Glu Leu Gln Glu 50 55
60 Leu Tyr Glu Gly Leu Arg Leu Asn Asn Met Asn Lys Tyr
Asp Tyr Val 65 70 75
80 Leu Thr Gly Tyr Thr Arg Asp Lys Ser Phe Leu Ala Met Val Val Asp
85 90 95 Ile Val Gln Glu
Leu Lys Gln Gln Asn Pro Arg Leu Val Tyr Val Cys 100
105 110 Asp Pro Val Leu Gly Asp Lys Trp Asp
Gly Glu Gly Ser Met Tyr Val 115 120
125 Pro Glu Asp Leu Leu Pro Val Tyr Lys Glu Lys Val Val Pro
Leu Ala 130 135 140
Asp Ile Ile Thr Pro Asn Gln Phe Glu Ala Glu Leu Leu Ser Gly Arg 145
150 155 160 Lys Ile His Ser Gln
Glu Glu Ala Leu Arg Val Met Asp Met Leu His 165
170 175 Ser Met Gly Pro Asp Thr Val Val Ile Thr
Ser Ser Asp Leu Pro Ser 180 185
190 Pro Gln Gly Ser Asn Tyr Leu Ile Val Leu Gly Ser Gln Arg Arg
Arg 195 200 205 Asn
Pro Ala Gly Ser Val Val Met Glu Arg Ile Arg Met Asp Ile Arg 210
215 220 Lys Val Asp Ala Val Phe
Val Gly Thr Gly Asp Leu Phe Ala Ala Met 225 230
235 240 Leu Leu Ala Trp Thr His Lys His Pro Asn Asn
Leu Lys Val Ala Cys 245 250
255 Glu Lys Thr Val Ser Thr Leu His His Val Leu Gln Arg Thr Ile Gln
260 265 270 Cys Ala
Lys Ala Gln Ala Gly Glu Gly Val Arg Pro Ser Pro Met Gln 275
280 285 Leu Glu Leu Arg Met Val Gln
Ser Lys Arg Asp Ile Glu Asp Pro Glu 290 295
300 Ile Val Val Gln Ala Thr Val Leu 305
310 138354PRTHomo sapiens 138Met Gly Cys Thr Leu Ser Ala Glu
Glu Arg Ala Ala Leu Glu Arg Ser 1 5 10
15 Lys Ala Ile Glu Lys Asn Leu Lys Glu Asp Gly Ile Ser
Ala Ala Lys 20 25 30
Asp Val Lys Leu Leu Leu Leu Gly Ala Gly Glu Ser Gly Lys Ser Thr
35 40 45 Ile Val Lys Gln
Met Lys Ile Ile His Glu Asp Gly Phe Ser Gly Glu 50
55 60 Asp Val Lys Gln Tyr Lys Pro Val
Val Tyr Ser Asn Thr Ile Gln Ser 65 70
75 80 Leu Ala Ala Ile Val Arg Ala Met Asp Thr Leu Gly
Ile Glu Tyr Gly 85 90
95 Asp Lys Glu Arg Lys Ala Asp Ala Lys Met Val Cys Asp Val Val Ser
100 105 110 Arg Met Glu
Asp Thr Glu Pro Phe Ser Ala Glu Leu Leu Ser Ala Met 115
120 125 Met Arg Leu Trp Gly Asp Ser Gly
Ile Gln Glu Cys Phe Asn Arg Ser 130 135
140 Arg Glu Tyr Gln Leu Asn Asp Ser Ala Lys Tyr Tyr Leu
Asp Ser Leu 145 150 155
160 Asp Arg Ile Gly Ala Ala Asp Tyr Gln Pro Thr Glu Gln Asp Ile Leu
165 170 175 Arg Thr Arg Val
Lys Thr Thr Gly Ile Val Glu Thr His Phe Thr Phe 180
185 190 Lys Asn Leu His Phe Arg Leu Phe Asp
Val Gly Gly Gln Arg Ser Glu 195 200
205 Arg Lys Lys Trp Ile His Cys Phe Glu Asp Val Thr Ala Ile
Ile Phe 210 215 220
Cys Val Ala Leu Ser Gly Tyr Asp Gln Val Leu His Glu Asp Glu Thr 225
230 235 240 Thr Asn Arg Met His
Glu Ser Leu Met Leu Phe Asp Ser Ile Cys Asn 245
250 255 Asn Lys Phe Phe Ile Asp Thr Ser Ile Ile
Leu Phe Leu Asn Lys Lys 260 265
270 Asp Leu Phe Gly Glu Lys Ile Lys Lys Ser Pro Leu Thr Ile Cys
Phe 275 280 285 Pro
Glu Tyr Thr Gly Pro Asn Thr Tyr Glu Asp Ala Ala Ala Tyr Ile 290
295 300 Gln Ala Gln Phe Glu Ser
Lys Asn Arg Ser Pro Asn Lys Glu Ile Tyr 305 310
315 320 Cys His Met Thr Cys Ala Thr Asp Thr Asn Asn
Ile Gln Val Val Phe 325 330
335 Asp Ala Val Thr Asp Ile Ile Ile Ala Asn Asn Leu Arg Gly Cys Gly
340 345 350 Leu Tyr
139354PRTHomo sapiens 139Met Gly Cys Thr Leu Ser Ala Glu Glu Arg Ala Ala
Leu Glu Arg Ser 1 5 10
15 Lys Ala Ile Glu Lys Asn Leu Lys Glu Asp Gly Ile Ser Ala Ala Lys
20 25 30 Asp Val Lys
Leu Leu Leu Leu Gly Ala Gly Glu Ser Gly Lys Ser Thr 35
40 45 Ile Val Lys Gln Met Lys Ile Ile
His Glu Asp Gly Phe Ser Gly Glu 50 55
60 Asp Val Lys Gln Tyr Lys Pro Val Val Tyr Ser Asn Thr
Ile Gln Ser 65 70 75
80 Leu Ala Ala Ile Val Arg Ala Met Asp Thr Leu Gly Ile Glu Tyr Gly
85 90 95 Asp Lys Glu Arg
Lys Ala Asp Ala Lys Met Val Cys Asp Val Val Ser 100
105 110 Arg Met Glu Asp Thr Glu Pro Phe Ser
Ala Glu Leu Leu Ser Ala Met 115 120
125 Met Arg Leu Trp Gly Asp Ser Gly Ile Gln Glu Cys Phe Asn
Arg Ser 130 135 140
Arg Glu Tyr Gln Leu Asn Asp Ser Ala Lys Tyr Tyr Leu Asp Ser Leu 145
150 155 160 Asp Arg Ile Gly Ala
Ala Asp Tyr Gln Pro Thr Glu Gln Asp Ile Leu 165
170 175 Arg Thr Arg Val Lys Thr Thr Gly Ile Val
Glu Thr His Phe Thr Phe 180 185
190 Lys Asn Leu His Phe Arg Leu Phe Asp Val Gly Gly Gln Arg Ser
Glu 195 200 205 Arg
Lys Lys Trp Ile His Cys Phe Glu Asp Val Thr Ala Ile Ile Phe 210
215 220 Cys Val Ala Leu Ser Gly
Tyr Asp Gln Val Leu His Glu Asp Glu Thr 225 230
235 240 Thr Asn Arg Met His Glu Ser Leu Lys Leu Phe
Asp Ser Ile Cys Asn 245 250
255 Asn Lys Trp Phe Thr Asp Thr Ser Ile Ile Leu Phe Leu Asn Lys Lys
260 265 270 Asp Ile
Phe Glu Glu Lys Ile Lys Lys Ser Pro Leu Thr Ile Cys Phe 275
280 285 Pro Glu Tyr Thr Gly Pro Ser
Ala Phe Thr Glu Ala Val Ala Tyr Ile 290 295
300 Gln Ala Gln Tyr Glu Ser Lys Asn Lys Ser Ala His
Lys Glu Ile Tyr 305 310 315
320 Thr His Val Thr Cys Ala Thr Asp Thr Asn Asn Ile Gln Phe Val Phe
325 330 335 Asp Ala Val
Thr Asp Val Ile Ile Ala Lys Asn Leu Arg Gly Cys Gly 340
345 350 Leu Tyr 14028PRThomo sapiens
140Cys Pro Asn Glu Phe Thr Gly Asp Arg Cys Gln Asn Tyr Val Met Ala 1
5 10 15 Ser Phe Tyr Lys
His Leu Gly Ile Glu Phe Met Glu 20 25
14120PRThomo sapiens 141Cys Pro Asn Glu Phe Thr Gly Asp Arg Cys Gln
Asn Tyr Val Met Ala 1 5 10
15 Ser Phe Tyr Lys 20 14230PRThomo sapiens 142Cys Pro
Asn Glu Phe Thr Gly Asp Arg Cys Gln Asn Tyr Val Met Ala 1 5
10 15 Ser Phe Tyr Ser Thr Ser Thr
Pro Phe Leu Ser Leu Pro Glu 20 25
30 14320PRThomo sapiens 143Cys Pro Asn Glu Phe Thr Gly Asp Arg Cys
Gln Asn Tyr Val Met Ala 1 5 10
15 Ser Phe Tyr Ser 20 14423PRThomo sapiens 144Cys
Gln Pro Gly Phe Thr Gly Ala Arg Cys Thr Glu Asn Val Pro Met 1
5 10 15 Lys Val Gln Asn Gln Glu
Lys 20 14523PRThomo sapiens 145Cys Gln Pro Gly
Phe Thr Gly Ala Arg Cys Thr Glu Asn Val Pro Met 1 5
10 15 Lys Val Gln Asn Gln Glu Ser
20 14631PRThomo sapiens 146Cys Gln Pro Gly Phe Thr Gly
Ala Arg Cys Thr Glu Asn Val Pro Met 1 5
10 15 Lys Val Gln Asn Gln Glu Lys His Leu Gly Ile
Glu Phe Ile Glu 20 25 30
14763PRThomo sapiens 147Ser His Leu Val Lys Cys Ala Glu Lys Glu Lys Thr
Phe Cys Val Asn 1 5 10
15 Gly Gly Glu Cys Phe Met Val Lys Asp Leu Ser Asn Pro Ser Arg Tyr
20 25 30 Leu Cys Lys
Cys Pro Asn Glu Phe Thr Gly Asp Arg Cys Gln Asn Tyr 35
40 45 Val Met Ala Ser Phe Tyr Lys His
Leu Gly Ile Glu Phe Met Glu 50 55
60 14855PRThomo sapiens 148Ser His Leu Val Lys Cys Ala Glu
Lys Glu Lys Thr Phe Cys Val Asn 1 5 10
15 Gly Gly Glu Cys Phe Met Val Lys Asp Leu Ser Asn Pro
Ser Arg Tyr 20 25 30
Leu Cys Lys Cys Pro Asn Glu Phe Thr Gly Asp Arg Cys Gln Asn Tyr
35 40 45 Val Met Ala Ser
Phe Tyr Lys 50 55 14965PRThomo sapiens 149Ser His
Leu Val Lys Cys Ala Glu Lys Glu Lys Thr Phe Cys Val Asn 1 5
10 15 Gly Gly Glu Cys Phe Met Val
Lys Asp Leu Ser Asn Pro Ser Arg Tyr 20 25
30 Leu Cys Lys Cys Pro Asn Glu Phe Thr Gly Asp Arg
Cys Gln Asn Tyr 35 40 45
Val Met Ala Ser Phe Tyr Ser Thr Ser Thr Pro Phe Leu Ser Leu Pro
50 55 60 Glu 65
15055PRThomo sapiens 150Ser His Leu Val Lys Cys Ala Glu Lys Glu Lys Thr
Phe Cys Val Asn 1 5 10
15 Gly Gly Glu Cys Phe Met Val Lys Asp Leu Ser Asn Pro Ser Arg Tyr
20 25 30 Leu Cys Lys
Cys Pro Asn Glu Phe Thr Gly Asp Arg Cys Gln Asn Tyr 35
40 45 Val Met Ala Ser Phe Tyr Ser
50 55 15158PRThomo sapiens 151Ser His Leu Val Lys Cys
Ala Glu Lys Glu Lys Thr Phe Cys Val Asn 1 5
10 15 Gly Gly Glu Cys Phe Met Val Lys Asp Leu Ser
Asn Pro Ser Arg Tyr 20 25
30 Leu Cys Lys Cys Gln Pro Gly Phe Thr Gly Ala Arg Cys Thr Glu
Asn 35 40 45 Val
Pro Met Lys Val Gln Asn Gln Glu Lys 50 55
15258PRThomo sapiens 152Ser His Leu Val Lys Cys Ala Glu Lys Glu Lys Thr
Phe Cys Val Asn 1 5 10
15 Gly Gly Glu Cys Phe Met Val Lys Asp Leu Ser Asn Pro Ser Arg Tyr
20 25 30 Leu Cys Lys
Cys Gln Pro Gly Phe Thr Gly Ala Arg Cys Thr Glu Asn 35
40 45 Val Pro Met Lys Val Gln Asn Gln
Glu Ser 50 55 15366PRThomo sapiens
153Ser His Leu Val Lys Cys Ala Glu Lys Glu Lys Thr Phe Cys Val Asn 1
5 10 15 Gly Gly Glu Cys
Phe Met Val Lys Asp Leu Ser Asn Pro Ser Arg Tyr 20
25 30 Leu Cys Lys Cys Gln Pro Gly Phe Thr
Gly Ala Arg Cys Thr Glu Asn 35 40
45 Val Pro Met Lys Val Gln Asn Gln Glu Lys His Leu Gly Ile
Glu Phe 50 55 60
Ile Glu 65 15452PRThomo sapiens 154Met Ser Glu Arg Lys Glu Gly Arg
Gly Lys Gly Lys Gly Lys Lys Lys 1 5 10
15 Glu Arg Gly Ser Gly Lys Lys Pro Glu Ser Ala Ala Gly
Ser Gln Ser 20 25 30
Pro Ala Leu Pro Pro Arg Leu Lys Glu Met Lys Ser Gln Glu Ser Ala
35 40 45 Ala Gly Ser Lys
50 15552PRThomo sapiens 155Met Ser Glu Arg Lys Glu Gly Arg Gly
Lys Gly Lys Gly Lys Lys Lys 1 5 10
15 Glu Arg Gly Ser Gly Lys Lys Pro Glu Ser Ala Ala Gly Ser
Gln Ser 20 25 30
Pro Ala Leu Pro Pro Gln Leu Lys Glu Met Lys Ser Gln Glu Ser Ala
35 40 45 Ala Gly Ser Lys
50 15691PRThomo sapiens 156Pro Gln Leu Lys Glu Met Lys Ser Gln
Glu Ser Ala Ala Gly Ser Lys 1 5 10
15 Leu Val Leu Arg Cys Glu Thr Ser Ser Glu Tyr Ser Leu Arg
Phe Lys 20 25 30
Trp Phe Lys Asn Gly Asn Glu Leu Asn Arg Lys Asn Lys Pro Gln Asn
35 40 45 Ile Lys Ile Gln
Lys Lys Pro Gly Lys Ser Glu Leu Arg Ile Asn Lys 50
55 60 Ala Ser Leu Ala Asp Ser Gly Glu
Tyr Met Cys Lys Val Ile Ser Lys 65 70
75 80 Leu Gly Asn Asp Ser Ala Ser Ala Asn Ile Thr
85 90 157126PRThomo sapiens 157 Ser Glu
Arg Lys Glu Gly Arg Gly Lys Gly Lys Gly Lys Lys Lys Glu 1 5
10 15 Arg Gly Ser Gly Lys Lys Pro
Glu Ser Ala Ala Gly Ser Gln Ser Pro 20 25
30 Ala Leu Pro Pro Gln Leu Lys Glu Met Lys Ser Gln
Glu Ser Ala Ala 35 40 45
Gly Ser Lys Leu Val Leu Arg Cys Glu Thr Ser Ser Glu Tyr Ser Leu
50 55 60 Arg Phe Lys
Trp Phe Lys Asn Gly Asn Glu Leu Asn Arg Lys Asn Lys 65
70 75 80 Pro Gln Asn Ile Lys Ile Gln
Lys Lys Pro Gly Lys Ser Glu Leu Arg 85
90 95 Ile Asn Lys Ala Ser Leu Ala Asp Ser Gly Glu
Tyr Met Cys Lys Val 100 105
110 Ile Ser Lys Leu Gly Asn Asp Ser Ala Ser Ala Asn Ile Thr
115 120 125 15863PRThomo sapiens
158Val Ile Ser Lys Leu Gly Asn Asp Ser Ala Ser Ala Asn Ile Thr Ile 1
5 10 15 Val Glu Ser Asn
Glu Ile Ile Thr Gly Met Pro Ala Ser Thr Glu Gly 20
25 30 Ala Tyr Val Ser Ser Glu Ser Pro Ile
Arg Ile Ser Val Ser Thr Glu 35 40
45 Gly Ala Asn Thr Ser Ser Ser Thr Ser Thr Ser Thr Thr Gly
Thr 50 55 60
1591342PRThomo sapiens 159Met Arg Ala Asn Asp Ala Leu Gln Val Leu Gly Leu
Leu Phe Ser Leu 1 5 10
15 Ala Arg Gly Ser Glu Val Gly Asn Ser Gln Ala Val Cys Pro Gly Thr
20 25 30 Leu Asn Gly
Leu Ser Val Thr Gly Asp Ala Glu Asn Gln Tyr Gln Thr 35
40 45 Leu Tyr Lys Leu Tyr Glu Arg Cys
Glu Val Val Met Gly Asn Leu Glu 50 55
60 Ile Val Leu Thr Gly His Asn Ala Asp Leu Ser Phe Leu
Gln Trp Ile 65 70 75
80 Arg Glu Val Thr Gly Tyr Val Leu Val Ala Met Asn Glu Phe Ser Thr
85 90 95 Leu Pro Leu Pro
Asn Leu Arg Val Val Arg Gly Thr Gln Val Tyr Asp 100
105 110 Gly Lys Phe Ala Ile Phe Val Met Leu
Asn Tyr Asn Thr Asn Ser Ser 115 120
125 His Ala Leu Arg Gln Leu Arg Leu Thr Gln Leu Thr Glu Ile
Leu Ser 130 135 140
Gly Gly Val Tyr Ile Glu Lys Asn Asp Lys Leu Cys His Met Asp Thr 145
150 155 160 Ile Asp Trp Arg Asp
Ile Val Arg Asp Arg Asp Ala Glu Ile Val Val 165
170 175 Lys Asp Asn Gly Arg Ser Cys Pro Pro Cys
His Glu Val Cys Lys Gly 180 185
190 Arg Cys Trp Gly Pro Gly Ser Glu Asp Cys Gln Thr Leu Thr Lys
Thr 195 200 205 Ile
Cys Ala Pro Gln Cys Asn Gly His Cys Phe Gly Pro Asn Pro Asn 210
215 220 Gln Cys Cys His Asp Glu
Cys Ala Gly Gly Cys Ser Gly Pro Gln Asp 225 230
235 240 Thr Asp Cys Phe Ala Cys Arg His Phe Asn Asp
Ser Gly Ala Cys Val 245 250
255 Pro Arg Cys Pro Gln Pro Leu Val Tyr Asn Lys Leu Thr Phe Gln Leu
260 265 270 Glu Pro
Asn Pro His Thr Lys Tyr Gln Tyr Gly Gly Val Cys Val Ala 275
280 285 Ser Cys Pro His Asn Phe Val
Val Asp Gln Thr Ser Cys Val Arg Ala 290 295
300 Cys Pro Pro Asp Lys Met Glu Val Asp Lys Asn Gly
Leu Lys Met Cys 305 310 315
320 Glu Pro Cys Gly Gly Leu Cys Pro Lys Ala Cys Glu Gly Thr Gly Ser
325 330 335 Gly Ser Arg
Phe Gln Thr Val Asp Ser Ser Asn Ile Asp Gly Phe Val 340
345 350 Asn Cys Thr Lys Ile Leu Gly Asn
Leu Asp Phe Leu Ile Thr Gly Leu 355 360
365 Asn Gly Asp Pro Trp His Lys Ile Pro Ala Leu Asp Pro
Glu Lys Leu 370 375 380
Asn Val Phe Arg Thr Val Arg Glu Ile Thr Gly Tyr Leu Asn Ile Gln 385
390 395 400 Ser Trp Pro Pro
His Met His Asn Phe Ser Val Phe Ser Asn Leu Thr 405
410 415 Thr Ile Gly Gly Arg Ser Leu Tyr Asn
Arg Gly Phe Ser Leu Leu Ile 420 425
430 Met Lys Asn Leu Asn Val Thr Ser Leu Gly Phe Arg Ser Leu
Lys Glu 435 440 445
Ile Ser Ala Gly Arg Ile Tyr Ile Ser Ala Asn Arg Gln Leu Cys Tyr 450
455 460 His His Ser Leu Asn
Trp Thr Lys Val Leu Arg Gly Pro Thr Glu Glu 465 470
475 480 Arg Leu Asp Ile Lys His Asn Arg Pro Arg
Arg Asp Cys Val Ala Glu 485 490
495 Gly Lys Val Cys Asp Pro Leu Cys Ser Ser Gly Gly Cys Trp Gly
Pro 500 505 510 Gly
Pro Gly Gln Cys Leu Ser Cys Arg Asn Tyr Ser Arg Gly Gly Val 515
520 525 Cys Val Thr His Cys Asn
Phe Leu Asn Gly Glu Pro Arg Glu Phe Ala 530 535
540 His Glu Ala Glu Cys Phe Ser Cys His Pro Glu
Cys Gln Pro Met Glu 545 550 555
560 Gly Thr Ala Thr Cys Asn Gly Ser Gly Ser Asp Thr Cys Ala Gln Cys
565 570 575 Ala His
Phe Arg Asp Gly Pro His Cys Val Ser Ser Cys Pro His Gly 580
585 590 Val Leu Gly Ala Lys Gly Pro
Ile Tyr Lys Tyr Pro Asp Val Gln Asn 595 600
605 Glu Cys Arg Pro Cys His Glu Asn Cys Thr Gln Gly
Cys Lys Gly Pro 610 615 620
Glu Leu Gln Asp Cys Leu Gly Gln Thr Leu Val Leu Ile Gly Lys Thr 625
630 635 640 His Leu Thr
Met Ala Leu Thr Val Ile Ala Gly Leu Val Val Ile Phe 645
650 655 Met Met Leu Gly Gly Thr Phe Leu
Tyr Trp Arg Gly Arg Arg Ile Gln 660 665
670 Asn Lys Arg Ala Met Arg Arg Tyr Leu Glu Arg Gly Glu
Ser Ile Glu 675 680 685
Pro Leu Asp Pro Ser Glu Lys Ala Asn Lys Val Leu Ala Arg Ile Phe 690
695 700 Lys Glu Thr Glu
Leu Arg Lys Leu Lys Val Leu Gly Ser Gly Val Phe 705 710
715 720 Gly Thr Val His Lys Gly Val Trp Ile
Pro Glu Gly Glu Ser Ile Lys 725 730
735 Ile Pro Val Cys Ile Lys Val Ile Glu Asp Lys Ser Gly Arg
Gln Ser 740 745 750
Phe Gln Ala Val Thr Asp His Met Leu Ala Ile Gly Ser Leu Asp His
755 760 765 Ala His Ile Val
Arg Leu Leu Gly Leu Cys Pro Gly Ser Ser Leu Gln 770
775 780 Leu Val Thr Gln Tyr Leu Pro Leu
Gly Ser Leu Leu Asp His Val Arg 785 790
795 800 Gln His Arg Gly Ala Leu Gly Pro Gln Leu Leu Leu
Asn Trp Gly Val 805 810
815 Gln Ile Ala Lys Gly Met Tyr Tyr Leu Glu Glu His Gly Met Val His
820 825 830 Arg Asn Leu
Ala Ala Arg Asn Val Leu Leu Lys Ser Pro Ser Gln Val 835
840 845 Gln Val Ala Asp Phe Gly Val Ala
Asp Leu Leu Pro Pro Asp Asp Lys 850 855
860 Gln Leu Leu Tyr Ser Glu Ala Lys Thr Pro Ile Lys Trp
Met Ala Leu 865 870 875
880 Glu Ser Ile His Phe Gly Lys Tyr Thr His Gln Ser Asp Val Trp Ser
885 890 895 Tyr Gly Val Thr
Val Trp Glu Leu Met Thr Phe Gly Ala Glu Pro Tyr 900
905 910 Ala Gly Leu Arg Leu Ala Glu Val Pro
Asp Leu Leu Glu Lys Gly Glu 915 920
925 Arg Leu Ala Gln Pro Gln Ile Cys Thr Ile Asp Val Tyr Met
Val Met 930 935 940
Val Lys Cys Trp Met Ile Asp Glu Asn Ile Arg Pro Thr Phe Lys Glu 945
950 955 960 Leu Ala Asn Glu Phe
Thr Arg Met Ala Arg Asp Pro Pro Arg Tyr Leu 965
970 975 Val Ile Lys Arg Glu Ser Gly Pro Gly Ile
Ala Pro Gly Pro Glu Pro 980 985
990 His Gly Leu Thr Asn Lys Lys Leu Glu Glu Val Glu Leu Glu
Pro Glu 995 1000 1005
Leu Asp Leu Asp Leu Asp Leu Glu Ala Glu Glu Asp Asn Leu Ala 1010
1015 1020 Thr Thr Thr Leu Gly
Ser Ala Leu Ser Leu Pro Val Gly Thr Leu 1025 1030
1035 Asn Arg Pro Arg Gly Ser Gln Ser Leu Leu
Ser Pro Ser Ser Gly 1040 1045 1050
Tyr Met Pro Met Asn Gln Gly Asn Leu Gly Glu Ser Cys Gln Glu
1055 1060 1065 Ser Ala
Val Ser Gly Ser Ser Glu Arg Cys Pro Arg Pro Val Ser 1070
1075 1080 Leu His Pro Met Pro Arg Gly
Cys Leu Ala Ser Glu Ser Ser Glu 1085 1090
1095 Gly His Val Thr Gly Ser Glu Ala Glu Leu Gln Glu
Lys Val Ser 1100 1105 1110
Met Cys Arg Ser Arg Ser Arg Ser Arg Ser Pro Arg Pro Arg Gly 1115
1120 1125 Asp Ser Ala Tyr His
Ser Gln Arg His Ser Leu Leu Thr Pro Val 1130 1135
1140 Thr Pro Leu Ser Pro Pro Gly Leu Glu Glu
Glu Asp Val Asn Gly 1145 1150 1155
Tyr Val Met Pro Asp Thr His Leu Lys Gly Thr Pro Ser Ser Arg
1160 1165 1170 Glu Gly
Thr Leu Ser Ser Val Gly Leu Ser Ser Val Leu Gly Thr 1175
1180 1185 Glu Glu Glu Asp Glu Asp Glu
Glu Tyr Glu Tyr Met Asn Arg Arg 1190 1195
1200 Arg Arg His Ser Pro Pro His Pro Pro Arg Pro Ser
Ser Leu Glu 1205 1210 1215
Glu Leu Gly Tyr Glu Tyr Met Asp Val Gly Ser Asp Leu Ser Ala 1220
1225 1230 Ser Leu Gly Ser Thr
Gln Ser Cys Pro Leu His Pro Val Pro Ile 1235 1240
1245 Met Pro Thr Ala Gly Thr Thr Pro Asp Glu
Asp Tyr Glu Tyr Met 1250 1255 1260
Asn Arg Gln Arg Asp Gly Gly Gly Pro Gly Gly Asp Tyr Ala Ala
1265 1270 1275 Met Gly
Ala Cys Pro Ala Ser Glu Gln Gly Tyr Glu Glu Met Arg 1280
1285 1290 Ala Phe Gln Gly Pro Gly His
Gln Ala Pro His Val His Tyr Ala 1295 1300
1305 Arg Leu Lys Thr Leu Arg Ser Leu Glu Ala Thr Asp
Ser Ala Phe 1310 1315 1320
Asp Asn Pro Asp Tyr Trp His Ser Arg Leu Phe Pro Lys Ala Asn 1325
1330 1335 Ala Gln Arg Thr
1340 1601308PRThomo sapiens 160Met Lys Pro Ala Thr Gly Leu Trp
Val Trp Val Ser Leu Leu Val Ala 1 5 10
15 Ala Gly Thr Val Gln Pro Ser Asp Ser Gln Ser Val Cys
Ala Gly Thr 20 25 30
Glu Asn Lys Leu Ser Ser Leu Ser Asp Leu Glu Gln Gln Tyr Arg Ala
35 40 45 Leu Arg Lys Tyr
Tyr Glu Asn Cys Glu Val Val Met Gly Asn Leu Glu 50
55 60 Ile Thr Ser Ile Glu His Asn Arg
Asp Leu Ser Phe Leu Arg Ser Val 65 70
75 80 Arg Glu Val Thr Gly Tyr Val Leu Val Ala Leu Asn
Gln Phe Arg Tyr 85 90
95 Leu Pro Leu Glu Asn Leu Arg Ile Ile Arg Gly Thr Lys Leu Tyr Glu
100 105 110 Asp Arg Tyr
Ala Leu Ala Ile Phe Leu Asn Tyr Arg Lys Asp Gly Asn 115
120 125 Phe Gly Leu Gln Glu Leu Gly Leu
Lys Asn Leu Thr Glu Ile Leu Asn 130 135
140 Gly Gly Val Tyr Val Asp Gln Asn Lys Phe Leu Cys Tyr
Ala Asp Thr 145 150 155
160 Ile His Trp Gln Asp Ile Val Arg Asn Pro Trp Pro Ser Asn Leu Thr
165 170 175 Leu Val Ser Thr
Asn Gly Ser Ser Gly Cys Gly Arg Cys His Lys Ser 180
185 190 Cys Thr Gly Arg Cys Trp Gly Pro Thr
Glu Asn His Cys Gln Thr Leu 195 200
205 Thr Arg Thr Val Cys Ala Glu Gln Cys Asp Gly Arg Cys Tyr
Gly Pro 210 215 220
Tyr Val Ser Asp Cys Cys His Arg Glu Cys Ala Gly Gly Cys Ser Gly 225
230 235 240 Pro Lys Asp Thr Asp
Cys Phe Ala Cys Met Asn Phe Asn Asp Ser Gly 245
250 255 Ala Cys Val Thr Gln Cys Pro Gln Thr Phe
Val Tyr Asn Pro Thr Thr 260 265
270 Phe Gln Leu Glu His Asn Phe Asn Ala Lys Tyr Thr Tyr Gly Ala
Phe 275 280 285 Cys
Val Lys Lys Cys Pro His Asn Phe Val Val Asp Ser Ser Ser Cys 290
295 300 Val Arg Ala Cys Pro Ser
Ser Lys Met Glu Val Glu Glu Asn Gly Ile 305 310
315 320 Lys Met Cys Lys Pro Cys Thr Asp Ile Cys Pro
Lys Ala Cys Asp Gly 325 330
335 Ile Gly Thr Gly Ser Leu Met Ser Ala Gln Thr Val Asp Ser Ser Asn
340 345 350 Ile Asp
Lys Phe Ile Asn Cys Thr Lys Ile Asn Gly Asn Leu Ile Phe 355
360 365 Leu Val Thr Gly Ile His Gly
Asp Pro Tyr Asn Ala Ile Glu Ala Ile 370 375
380 Asp Pro Glu Lys Leu Asn Val Phe Arg Thr Val Arg
Glu Ile Thr Gly 385 390 395
400 Phe Leu Asn Ile Gln Ser Trp Pro Pro Asn Met Thr Asp Phe Ser Val
405 410 415 Phe Ser Asn
Leu Val Thr Ile Gly Gly Arg Val Leu Tyr Ser Gly Leu 420
425 430 Ser Leu Leu Ile Leu Lys Gln Gln
Gly Ile Thr Ser Leu Gln Phe Gln 435 440
445 Ser Leu Lys Glu Ile Ser Ala Gly Asn Ile Tyr Ile Thr
Asp Asn Ser 450 455 460
Asn Leu Cys Tyr Tyr His Thr Ile Asn Trp Thr Thr Leu Phe Ser Thr 465
470 475 480 Ile Asn Gln Arg
Ile Val Ile Arg Asp Asn Arg Lys Ala Glu Asn Cys 485
490 495 Thr Ala Glu Gly Met Val Cys Asn His
Leu Cys Ser Ser Asp Gly Cys 500 505
510 Trp Gly Pro Gly Pro Asp Gln Cys Leu Ser Cys Arg Arg Phe
Ser Arg 515 520 525
Gly Arg Ile Cys Ile Glu Ser Cys Asn Leu Tyr Asp Gly Glu Phe Arg 530
535 540 Glu Phe Glu Asn Gly
Ser Ile Cys Val Glu Cys Asp Pro Gln Cys Glu 545 550
555 560 Lys Met Glu Asp Gly Leu Leu Thr Cys His
Gly Pro Gly Pro Asp Asn 565 570
575 Cys Thr Lys Cys Ser His Phe Lys Asp Gly Pro Asn Cys Val Glu
Lys 580 585 590 Cys
Pro Asp Gly Leu Gln Gly Ala Asn Ser Phe Ile Phe Lys Tyr Ala 595
600 605 Asp Pro Asp Arg Glu Cys
His Pro Cys His Pro Asn Cys Thr Gln Gly 610 615
620 Cys Asn Gly Pro Thr Ser His Asp Cys Ile Tyr
Tyr Pro Trp Thr Gly 625 630 635
640 His Ser Thr Leu Pro Gln His Ala Arg Thr Pro Leu Ile Ala Ala Gly
645 650 655 Val Ile
Gly Gly Leu Phe Ile Leu Val Ile Val Gly Leu Thr Phe Ala 660
665 670 Val Tyr Val Arg Arg Lys Ser
Ile Lys Lys Lys Arg Ala Leu Arg Arg 675 680
685 Phe Leu Glu Thr Glu Leu Val Glu Pro Leu Thr Pro
Ser Gly Thr Ala 690 695 700
Pro Asn Gln Ala Gln Leu Arg Ile Leu Lys Glu Thr Glu Leu Lys Arg 705
710 715 720 Val Lys Val
Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys Gly Ile 725
730 735 Trp Val Pro Glu Gly Glu Thr Val
Lys Ile Pro Val Ala Ile Lys Ile 740 745
750 Leu Asn Glu Thr Thr Gly Pro Lys Ala Asn Val Glu Phe
Met Asp Glu 755 760 765
Ala Leu Ile Met Ala Ser Met Asp His Pro His Leu Val Arg Leu Leu 770
775 780 Gly Val Cys Leu
Ser Pro Thr Ile Gln Leu Val Thr Gln Leu Met Pro 785 790
795 800 His Gly Cys Leu Leu Glu Tyr Val His
Glu His Lys Asp Asn Ile Gly 805 810
815 Ser Gln Leu Leu Leu Asn Trp Cys Val Gln Ile Ala Lys Gly
Met Met 820 825 830
Tyr Leu Glu Glu Arg Arg Leu Val His Arg Asp Leu Ala Ala Arg Asn
835 840 845 Val Leu Val Lys
Ser Pro Asn His Val Lys Ile Thr Asp Phe Gly Leu 850
855 860 Ala Arg Leu Leu Glu Gly Asp Glu
Lys Glu Tyr Asn Ala Asp Gly Gly 865 870
875 880 Lys Met Pro Ile Lys Trp Met Ala Leu Glu Cys Ile
His Tyr Arg Lys 885 890
895 Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Ile Trp Glu
900 905 910 Leu Met Thr
Phe Gly Gly Lys Pro Tyr Asp Gly Ile Pro Thr Arg Glu 915
920 925 Ile Pro Asp Leu Leu Glu Lys Gly
Glu Arg Leu Pro Gln Pro Pro Ile 930 935
940 Cys Thr Ile Asp Val Tyr Met Val Met Val Lys Cys Trp
Met Ile Asp 945 950 955
960 Ala Asp Ser Arg Pro Lys Phe Lys Glu Leu Ala Ala Glu Phe Ser Arg
965 970 975 Met Ala Arg Asp
Pro Gln Arg Tyr Leu Val Ile Gln Gly Asp Asp Arg 980
985 990 Met Lys Leu Pro Ser Pro Asn Asp
Ser Lys Phe Phe Gln Asn Leu Leu 995 1000
1005 Asp Glu Glu Asp Leu Glu Asp Met Met Asp Ala
Glu Glu Tyr Leu 1010 1015 1020
Val Pro Gln Ala Phe Asn Ile Pro Pro Pro Ile Tyr Thr Ser Arg
1025 1030 1035 Ala Arg Ile
Asp Ser Asn Arg Ser Glu Ile Gly His Ser Pro Pro 1040
1045 1050 Pro Ala Tyr Thr Pro Met Ser Gly
Asn Gln Phe Val Tyr Arg Asp 1055 1060
1065 Gly Gly Phe Ala Ala Glu Gln Gly Val Ser Val Pro Tyr
Arg Ala 1070 1075 1080
Pro Thr Ser Thr Ile Pro Glu Ala Pro Val Ala Gln Gly Ala Thr 1085
1090 1095 Ala Glu Ile Phe Asp
Asp Ser Cys Cys Asn Gly Thr Leu Arg Lys 1100 1105
1110 Pro Val Ala Pro His Val Gln Glu Asp Ser
Ser Thr Gln Arg Tyr 1115 1120 1125
Ser Ala Asp Pro Thr Val Phe Ala Pro Glu Arg Ser Pro Arg Gly
1130 1135 1140 Glu Leu
Asp Glu Glu Gly Tyr Met Thr Pro Met Arg Asp Lys Pro 1145
1150 1155 Lys Gln Glu Tyr Leu Asn Pro
Val Glu Glu Asn Pro Phe Val Ser 1160 1165
1170 Arg Arg Lys Asn Gly Asp Leu Gln Ala Leu Asp Asn
Pro Glu Tyr 1175 1180 1185
His Asn Ala Ser Asn Gly Pro Pro Lys Ala Glu Asp Glu Tyr Val 1190
1195 1200 Asn Glu Pro Leu Tyr
Leu Asn Thr Phe Ala Asn Thr Leu Gly Lys 1205 1210
1215 Ala Glu Tyr Leu Lys Asn Asn Ile Leu Ser
Met Pro Glu Lys Ala 1220 1225 1230
Lys Lys Ala Phe Asp Asn Pro Asp Tyr Trp Asn His Ser Leu Pro
1235 1240 1245 Pro Arg
Ser Thr Leu Gln His Pro Asp Tyr Leu Gln Glu Tyr Ser 1250
1255 1260 Thr Lys Tyr Phe Tyr Lys Gln
Asn Gly Arg Ile Arg Pro Ile Val 1265 1270
1275 Ala Glu Asn Pro Glu Tyr Leu Ser Glu Phe Ser Leu
Lys Pro Gly 1280 1285 1290
Thr Val Leu Pro Pro Pro Pro Tyr Arg His Arg Asn Thr Val Val 1295
1300 1305
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